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P5091 affects apoptotic process

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P5091 activates apoptotic process.

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P5091 activates apoptotic process. 10 / 37

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"P5091 treatment effectively induces apoptosis in both TP53 mutated MEC-1 and TP53-wild-type EHEB cell lines and, remarkably, is highly effective in del17p CLL primary CD19 + lymphocytes, with an apoptotic induction ' potency ' like the one observed in TP53-wild type CLL samples."

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"Notable examples include FOXO-DRI, which activates FOXO transcription factors involved in regulating the cell cycle and apoptosis [219]; UBX0101, known for its ability to selectively induce apoptosis in senescent cells, offering therapeutic promise for age-related diseasesm [219]; and P22077/P5091, which inhibit MDM2 to enhance P53 activity and promote the removal of senescent cells [220]."

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"P5091 is an inhibitor of USP7 and USP47 ( Chauhan et al., 2012; Weinstock et al., 2012 ) and was found to induce apoptosis of multiple myeloma cells resistant to the 20S proteasome inhibitor bortezomi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Meanwhile, P5091 induced apoptosis in multiple myeloma cells resistant to conventional and Bortezomib therapies."

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"The Z-VAD-FMK pan-caspase inhibitor interfered with the P5091 induced citotoxicity in SCLC cells; moreover, the caspase 3 is activated upon P5091 treatment of SCLC cells, overall suggesting that the a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"The detection at western blot of the cleaved fragments of cytochrome C and caspase 8 suggests that the P5091 triggered apoptosis was mediated either in mitochondria dependent and mitochondria independ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Taken together, all data demonstrated that the low dose P5091 induced apoptosis via the activation of the p53 pathway in senescent HDF cells.The progression of wound closure following the topical appl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"P5091 induced apoptosis in BTZ resistant MM cells, supporting the concept that alternate (upstream) targeting of the UPS has potential utility in cancer therapy."

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"Moreover, the deubiquitinase USP7 has been shown to deubiquitinate several key cancer proteins, and P5091, a highly specific inhibitor of USP7, induced apoptosis in multiple myeloma cells."

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"26 The E3 inhibitor lenalidomide , which targets MARCH 1 , has been used to treat hematologic malignancies ; 88 the DUB inhibitor curcumin destabilizes CSN5 and improves the efficacy of immunotherapy in breast cancer , melanoma , and colon cancer ; 53 P5091 , which targets USP7 , induces apoptosis in multiple myeloma cell lines.134 Given the success of these E3 inhibitors and DUB inhibitors , increasing efforts have been made to design and develop novel small molecule inhibitors that are expected to modulate immune checkpoint pathways ."

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P5091 activates apoptotic process. 1 / 1

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"Another selective USP7 inhibitor , P5091 ( Fig. 2L ) , was able to induce apoptosis in multiple myeloma cells resistant to conventional and Bortezomib therapies [ 120 ] ."

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P5091 inhibits apoptotic process.

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P5091 inhibits apoptotic process. 10 / 12

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"The small molecule inhibitor, P5091, is an inhibitor of USP7 and induces apoptosis in Multiple Myeloma cells [12]."

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"Inhibition of Usp7 with the selective inhibitor P5091 induces apoptosis in MM cells resistant to conventional therapy and acts synergistically with the HDAC inhibitor SAHA, lenalidomide and dexamethasone."

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"The USP7 inhibitor P5091 induces apoptosis in GBM cells."

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"We first determined that the USP7 inhibitor P5091 reduced cells growth in two SCLC H526 and H209 cell lines, by inducing apoptosis."

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"P5091 has also been reported to inhibit colorectal tumor growth in an HCT116 xenograft mouse model by suppressing proliferation and inducing apoptosis in CRC cells [221]."

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"One such inhibitor, P5091, is highly selective against USP7 and has been shown to induce apoptotic cell death in therapy resistant multiple myeloma cells ."

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"The USP7 inhibitor P5091 has been reported to induce apoptosis of multiple myeloma (MM) cells, and synergistic anti-MM effects can be exerted by multiple drugs."

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"The DUB inhibitors P5091 and WP1130 could significantly induce apoptosis in both naïve and PI‐tolerant cells to varying degrees (Figure S2A)."

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"Furthermore, a selective USP7 inhibitor, P5091, was found to induce apoptosis in multiple myeloma cells that are resistant to conventional anti-cancer therapies [XREF_BIBR]."

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"Another selective USP7 inhibitor, P5091 (Fig. 2L), was able to induce apoptosis in multiple myeloma cells resistant to conventional and Bortezomib therapies [120].2.5.3 USP14 inhibitor."

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P5091 affects USP7

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P5091 inhibits USP7.

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P5091 inhibits USP7. 10 / 38

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"P5091 (inhibitor of USP7) and b-AP15 (inhibitor of USP14/UCHL5) inhibit the growth of bortezomib-resistant multiple myeloma [41,42,]."

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"The binding of P5091 in this state possibly block USP7 into auto-inhibited state by reducing the elasticity of the pocket residues drastically."

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"P5091 can effectively block the deubiquitinating activity of USP7, leading to the destabilization of its oncogenic substrates such as FOXM1, oncoprotein SE translocation (SET), and N-myc [27, 52, 53]."

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"Chauhan et al 14 discovered that P5091 was a specific inhibitor of deubiquitylating enzyme USP7."

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"Moreover, the inhibition of USP7 by P5091 accelerated the degradation of CCDC6 versus control in cycloheximide treated SCLC cells in vitro and sensitized the cells to PARP inhibitors alone and in combination with cisplatin (71)."

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"After USP7 inhibition by P5091, the PE decreased significantly in both cell lines analyzed."

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"As expected, mice in which USP7 activity was inhibited by P5091 showed dramatically increased susceptibility to Salmonella typhimurium."

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"P5091 , as an inhibitor of USP7 , actively inhibits USP7 , resulting in increased steady-state protein levels of p53 and p21 ."

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"The study has also suggested that P5091 inhibits USP7 activity without blocking proteasome function directly."

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P5091 activates USP7.

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P5091 activates USP7. 4 / 4

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"The USP7 inhibitors, HBX 19,818 and P5091, were previously reported to selectively inhibit USP7 in vitro and in vivo, and importantly, P5091 showed cytotoxicity in relapsed MM cells derived from cancer patients (Chauhan et al., 2012; Reverdy et al., 2012)."

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"At present, a variety of small molecular inhibitors, natural compounds and small molecular peptides against USP7 have shown specific USP7 inhibition and certain anti-tumor activity [20], such as USP7 inhibitor P5091 [28], which can reduce Wnt signal pathway activity by enhancing ubiquitin-mediated degradation of β-catenin.c-Myc plays a pivotal role in the Warburg effect."

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"These inhibitors, and particularly P5091 and P22077, have been shown to induce degradation of many USP7 substrates and phenocopy USP7 knockdown."

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"Another USP7 inhibitor, P5091 selectively inhibits USP7 both in vitro and in vivo 89."

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P5091 increases the amount of USP7.

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P5091 increases the amount of USP7. 1 / 1

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"Analysis of SRSF6 levels showed that the combination of CHX and P5091 treatment leads to a faster decrease in SRSF6 levels compared to CHX alone, suggesting USP7 controls protein level of SRSF6 irrespective of potential effects on SRSF6 gene transcription (XREF_FIG)."

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P5091 affects TP53

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P5091 increases the amount of TP53.

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P5091 increases the amount of TP53. 6 / 6

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"P5091 (XREF_TABLE) actively inhibits USP7 at concentrations as low as 5-10 microM in the cellular environment, resulting in HDM2 polyubiquitination and accelerated degradation by the proteasome, and consequently increased steady-state protein levels of p53 and p21."

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"P5091 increased p53 and p21 protein levels in a time dependent fashion in the wild-type TP53 cells, TC32 and TC138 (XREF_FIG)."

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"6 This suggests that although P5091 increases p53 levels, its cytotoxic activity is not solely dependent on p53, indicating that P5091-induced cytotoxicity is mediated only in part via p53."

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"Further, we found through flow cytometry that a low dose of P5091 can cause early apoptosis of senescent HDF cells ( Fig. 3 E and G) and increase the expression of the apoptosis marker c-PARP1 and the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Mechanistic studies further show that P5091 triggered apoptosis in MM cells is associated with 1) activation of caspase-8, caspase-9, caspase-3, and PARP; and 2) downregulation of USP7 substrate HDM2, as well as increased expression of p53 and p21."

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"P53 levels were slightly increased by HDM2-siRNA knockdown, and further upregulated by P5091 treatment."

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P5091 increases the amount of mutated TP53. 1 / 1

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"Furthermore, USP7 inhibitor P5091 also diminished CCSCs self-renewal and reduced mutant p53 levels."

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P5091 activates TP53.

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P5091 activates TP53. 5 / 5

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"P5091 downregulated MDM2 and upregulated p53 in WI‐38 SnCs but not in WI‐38 non‐SnCs (Figure 1c)."

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"In addition to PTEN, p53 is upregulated by P5091, but its cytotoxic activity is not dependent on p53 ."

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"(A) Surviving fractions of HCT116 p53-/- cells, compared to the p53 wild type, treated with olaparib, P5091 or the combination of the two drugs at the indicated doses for 72 h are shown (the plotted v[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Notably, melatonin induced a marked reduction in proliferation of p53 wild-type NSCLC cells (Fig. 6F) while the combination of P5091 and melatonin elicited strong growth inhibition of p53-deficient NSCLC cells (Fig. 6G)."

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P5091 decreases the amount of TP53.

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P5091 decreases the amount of TP53. 3 / 3

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"In concert with these data, P5091 downregulated HDM2 and HDMX, as well as upregulated p53 and p21 levels, in scr-siRNA-transfected cells (XREF_SUPPLEMENTARY)."

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"P5091 decreased HDM2 and HDMX, as well as upregulated p53 and p21 levels (XREF_FIG)."

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"P5091 actively inhibits USP7 at concentrations as low as 5 - 10 muM in the cellular environment, resulting in HDM2 poly-ubiquitination and accelerated degradation by the proteasome, and consequently increased steady-state protein levels of p53 and p21."

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P5091 phosphorylates TP53.

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P5091 leads to the phosphorylation of TP53. 1 / 1

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"Imatinib and P5091 promote p53 upregulation and phosphorylation."

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P5091 inhibits TP53.

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P5091 inhibits TP53. 1 / 1

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"It is worthy to note that P5091 can induce the apoptosis of Caco-2 cells deficient in p53."

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P5091 affects Neoplasms

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P5091 inhibits Neoplasms.

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P5091 inhibits Neoplasms. 9 / 9

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"In the mouse xenograft model studies, P5091 was well tolerated and inhibited tumor growth associated with downregulated Wnt signaling."

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"All of these results proved that both P5091 and anti-PD-1 treatment enhanced tumor proliferation inhibition and apoptosis in vivo."

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"In a transgenic mouse model of PDAC, named KPC, P5091 effectively blocks tumor progression."

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"P5091 has been shown to inhibit tumor growth by inhibiting USP7 and USP47 and is well tolerated in animals [107] ."

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"In addition, P5091 inhibits tumor growth and synergizes with other chemotherapeutic agents such as lenalidomide, HDAC inhibitor or dexamethasone to induce synergistic anti-multiple myeloma effect [32, 33]."

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"P5091 was reported to be well tolerated by animals and to inhibit tumor growth ( Chauhan et al., 2012 )."

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"In multiple myeloma cell lines, P5091 stabilized p53 and inhibited tumor growth, and prolonged survival as a single agent in xenograft studies."

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"P5091 treatment inhibited melanoma tumor growth Figure 7 F)."

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"In the HCT116 xenograft mouse model, P5091 also inhibited tumor growth in vivo, which was consistently associated with decreased expression of β-catenin and Wnt target genes."

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P5091 activates Neoplasms.

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P5091 activates Neoplasms. 6 / 6

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"The USP7 inhibitor P5091 has been demonstrated to effectively inhibit Wnt signaling and tumor growth, underscoring the pivotal role of USP7 in this context [28]."

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"For example, P5091 was able to induce apoptosis in non-neuroendocrine lung (L-NEC) tumor while P22077 reactivated p53 and induced apoptosis in human neuroblastoma (NB) and overcame cellular chemoresis[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"When evaluated in mice with Lewis lung carcinoma, USP7 inhibitor P5091 slowed tumor growth and promoted the infiltration of M1 macrophages and IFN-γ-expressing CD8+ T cells."

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"For p53-deficient NSCLC, combination treatment with melatonin and the USP7 inhibitor P5091 could significantly inhibit tumor growth."

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"Administration of USP7 inhibitor P5091 (25 mg/kg) has been found to decrease the growth rate of tumor in vivo."

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"Furthermore, P5091 treatment caused FOXP3 loss in Treg cells decreased the proportion of Treg cells in tumor bearing mice."

30697058

P5091 affects Multiple Myeloma

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P5091 activates Multiple Myeloma.

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"The first USP7 inhibitor, P5091, was previously shown to inhibit multiple myeloma proliferation [31]."

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"P5091 was found to induce apoptosis in various MM cell lines as well as ex vivo cells, including those resistant to previous treatments [XREF_BIBR]."

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"Datas indicated that the USP7 inhibitor P5091 was overcoming bortezomib resistance in multiple myelomas by destabilizing NEK2 [30]."

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"Since our in vitro data showed that P5091 triggers apoptosis in p53-null ARP-1 MM cells, we evaluated whether P5091 similarly affects the growth of ARP-1 cells in vivo."

22975377

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"P5091 induces apoptosis of multiple myeloma cells that are resistant to bortezomib, a 20S proteasome inhibitor."

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"P5091 triggers apoptosis in MM cells even in the presence of the MM-host BM microenvironment."

22975377

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"These data suggest that P5091 not only directly targets MM cells, but also overcomes the cytoprotective effects of the MM-host BM microenvironment."

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"P5091 suppressed in vivo tumor growth [XREF_BIBR], caused apoptosis of Multiple Myeloma (MM) cells, and prolonged survival in xenograft models [XREF_BIBR]."

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P5091 inhibits Multiple Myeloma.

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"P5091 inhibits human MM cell growth in vivo and prolongs survival in the MM.1 S MM xenograft mouse model."

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"For instance, the USP7 inhibitor P5091 in combination with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic antitumor activity in multiple myeloma [ 133 ]."

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"One such inhibitor, P5091, is highly selective against USP7 and has been shown to induce apoptotic cell death in therapy resistant multiple myeloma cells ."

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"The USP7 inhibitor P5091 has been reported to induce apoptosis of multiple myeloma (MM) cells, and synergistic anti-MM effects can be exerted by multiple drugs."

32002017

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"P5091 inhibits USP7 deubiquitylating activity, without blocking proteasome activity, in MM cells."

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"P5091 blocks the USP7 activity in MM at the IC 50 of P5091 for these cells (XREF_FIG and data not shown)."

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"P22077 and P5091, two HAUSP inhibitors discovered by high-throughput screens, were demonstrated to inhibit neuroblastoma or multiple myeloma growth in vivo, respectively (Chauhan et al., 2012; Fan et al., 2013)."

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P5091 affects cell population proliferation

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P5091 inhibits cell population proliferation.

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"The USP7 selective small-molecule inhibitors P5091 and P22077 inhibited cell proliferation and induced megakaryocytic differentiation in both cell lines and primary cells."

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"P5091 decreases proliferation in harvested tumors, as assessed by BrdU and Ki67 staining (XREF_FIG, and XREF_SUPPLEMENTARY)."

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"P5091 has also been reported to inhibit colorectal tumor growth in an HCT116 xenograft mouse model by suppressing proliferation and inducing apoptosis in CRC cells [221]."

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"Co-treatment with P5091 and melatonin significantly suppressed H1299 cell proliferation (Fig. 6D, E)."

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"Tumor cell proliferation was downregulated by P5091 and anti-PD-1 treatment as evidenced by hematoxylin and eosin stain (H&E) and proliferating cell nuclear antigen (PCNA) immunohistochemistry staining."

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"P5091 inhibited HCT166 proliferation [86] , whereas P22077 downregulated the USP7 targets MDM2, claspin, and Checkpoint kinase 1 (Chk1) and inhibited neuroblastoma growth [75] ."

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"All of these results proved that both P5091 and anti-PD-1 treatment enhanced tumor proliferation inhibition and apoptosis in vivo."

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"Interestingly, both P5091 and P22077 treatment apparently blocked Daoy cell proliferation and metastasis ( Fig. 4 A and B)."

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"Taken together, these results are consistent with the findings shown in the cultured cells, suggesting that P5091 inhibits the Wnt signaling and proliferation of colon cancer cells both in vitro and i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"P5091 treatment inhibited BMSCs induced proliferation of MM.1 S (XREF_FIG)."

22975377

P5091 activates cell population proliferation.

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P5091 activates cell population proliferation. 1 / 1

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"The first USP7 inhibitor, P5091, was previously shown to inhibit multiple myeloma proliferation [31]."

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P5091 affects MDM2

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P5091 inhibits MDM2.

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P5091 inhibits MDM2. 10 / 10

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"Co-immunoprecipitation assays show that HDM2 is associated with p21 in MM cells, and that P5091 downregualates HDM2 and upregualtes p21 (XREF_FIG)."

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"P5091 downregulated MDM2 and upregulated p53 in WI‐38 SnCs but not in WI‐38 non‐SnCs (Figure 1c)."

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"Examination of harvested tumors showed that P5091 inhibited USP7 activity, decreased HDM2, and increased p21 levels relative to tumors from control mice (XREF_FIG)."

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"P5091 accelerates the degradation of HDM2 versus control cycloheximide (CHX) alone treated U20S cells (XREF_FIG)."

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"Likewise, P5091 enhanced the degradation of HDM2 in prostate cancer cell lines (XREF_SUPPLEMENTARY)."

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"The functional specificity of P5091 is confirmed using different strategies : first, cell-free based experiments using a reporter (Ub-PLA 2)-based assay demonstrate a potent, specific, and selective inhibition of USP7 activity by P5091; second, P5091 enhances degradation of its primary substrate HDM2; third, USP7 KO in HCT-116 cells confers resistance to P5091; and fourth, P5091 blocks USP7 DUB activity without altering proteasome activity."

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"Western blot analysis revealed that P5091 decreased the level of MDM2 protein that is otherwise induced by ATSP-7041 as a result of the surge in p53 and counter-up-regulation of MDM2 (XREF_FIG)."

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"22 Combination of RRx-001 and P5091 markedly decreased HDM2, upregulated p53 and p21 versus either agent alone (XREF_FIG)."

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"For example, in the case of ATSP-7041 and P5091 treatment, the addition of P5091 suppresses the counter up-regulation of MDM2."

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P5091 ubiquitinates MDM2.

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P5091 leads to the ubiquitination of MDM2. 2 / 2

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"Importantly, addition of P5091 markedly increases HDM2 ubiquitination, in particular, the band between 130-170 (lane 3 versus lane 4)."

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"In agreement with our results using U20S cells (XREF_FIG), P5091 increases ubiquitination of endogenous HDM2 in MM.1 S cells (XREF_SUPPLEMENTARY)."

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P5091 deubiquitinates MDM2.

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"As expected, both genetic ablation of USP7 gene (siRNA or somatic knockout) and pharmacological inhibition of USP7 protein (P5091) prevents USP7 from deubiquitinating HDM2, resulting in stabilization and accumulation of p53, as well as p21-induced growth arrest and cell death (Chauhan et al., 2012)."

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P5091 activates MDM2.

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"The P5091 induced HDM2 degradation was blocked in the presence of proteasome inhibitor MG132 (XREF_SUPPLEMENTARY), suggesting that HDM2 degradation is proteasome dependent."

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P5091 affects CCDC6

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P5091 inhibits CCDC6.

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"In a recent study, P5091, an inhibitor of USP7, promoted CCDC6 degradation and sensitized bladder cancer cells to the cytotoxic effect of the PARP-inhibitor olaparib (128)."

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"In order to evaluate whether the new epigenetic agent RRx-001, that induce DNA damage through the release of reactive oxygen or nitrogen species, combined with P5091, that downregulates CCDC6 and impairs HR-DNA repair, might increase the sensitivity to PARPi in urothelial carcinoma cells, we treated the bladder cancer cells with different concentrations of the PARP-inhibitor Olaparib and with fixed doses of P5091 and RRx-001."

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"Generally, CCDC6 downregulation by P5091 improved sensitivity to olaparib in all cell lines herein analysed."

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"Notably, the CCDC6 downregulation by P5091 treatment affected PARGi-induced cytotoxicity (in the presence of P5091 at 2.5 μM, the IC50 raised to 1.33 μM ± 0.32) (Fig. 3A)."

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"The P5091 accelerated the degradation of CCDC6 in PC3 cells and LNCaP versus control cycloheximide alone treated."

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"Interestingly, in the presence of P5091, which increases the CCDC6 degradation, the combined treatment of cisplatin and olaparib turned into an additive effect in OV-90olaR cells (CI = 1) (Fig. 4E)."

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"Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays."

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"Moreover, P5091 accelerated the degradation of CCDC6 sensitizing the cells to PARP-inhibitors, that acted sinergistically with genotoxic agents."

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"Moreover, in high-grade urothelial bladder cancer, the CCDC6 degradation caused by P5091 making bladder cancer cells more sensitive to PARP-inhibitor drugs [86]."

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"Thus, P5091 accelerated the degradation of CCDC6 versus control cycloheximide alone treated H526 and H209 L-NET cells."

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P5091 increases the amount of CCDC6.

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"P5091 also enhances the sensitivity of lung neuroendocrine tumor cells to PARP inhibitors by diminishing CCDC6 levels and hampering HR repair, showing combined efficacy against lung neuroendocrine and CRPC [145, 147]."

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P5091 deubiquitinates CCDC6.

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P5091 leads to the deubiquitination of CCDC6. 1 / 1

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"In addition, after targeting USP7, USP7 inhibitor P5091 stimulates the ubiquitination of CCDC6, induces its degradation, and increases the sensitivity of pulmonary neuroendocrine tumors to PARP inhibi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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P5091 activates CCDC6.

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P5091 activates CCDC6. 1 / 1

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"Notably, by adding back ectopic wt CCDC6 plasmid to the LNCaP treated with P5091, we were able to rescue the weak sensitivity to olaparib, in terms of 50% inhibitor concentration values (IC50) (XREF_SUPPLEMENTARY), suggesting a pivotal role of CCDC6 as a USP7 substrate."

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P5091 affects CDKN1A

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P5091 increases the amount of CDKN1A.

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"Second, P5091 treatment decreases the viability of p53-null ARP-1 MM cells (XREF_FIG), associated with decreased HDM2 levels and increased p21 expression (XREF_FIG, inset)."

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"P5091 increased p53 and p21 protein levels in a time dependent fashion in the wild-type TP53 cells, TC32 and TC138 (XREF_FIG)."

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"Notably, P5091 treatment decreased the viability of p53 null ARP-1 MM cells, associated with decreased Mdm2 levels and increased p21 expression."

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P5091 decreases the amount of CDKN1A.

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"P5091 decreased HDM2 and HDMX, as well as upregulated p53 and p21 levels (XREF_FIG)."

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"In concert with these data, P5091 downregulated HDM2 and HDMX, as well as upregulated p53 and p21 levels, in scr-siRNA-transfected cells (XREF_SUPPLEMENTARY)."

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P5091 inhibits CDKN1A.

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P5091 inhibits CDKN1A. 1 / 1

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"Co-immunoprecipitation assays show that HDM2 is associated with p21 in MM cells, and that P5091 downregualates HDM2 and upregualtes p21 (XREF_FIG)."

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P5091 activates CDKN1A.

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P5091 activates CDKN1A. 1 / 1

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"Our data show that besides p53, P5091 treatment also upregulates p21, a known downstream target of HDM2-p53 axis."

22975377

P5091 affects USP47

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P5091 inhibits USP47.

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P5091 inhibits USP47. 6 / 6

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"P5091 has been recently reported to also inhibit USP47, one deubiquitinase most closely related to USP7 [27] ."

28216017

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"These compounds were found to be highly selective for USP7 in counter-screening against a panel of DUBs including USP10 and USP47, which are also inhibited by P5091."

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"For example, P22077 and P5091 also inhibited USP47 with similar potency [10,77,83,87] ."

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"P5091 has been shown to inhibit tumor growth by inhibiting USP7 and USP47 and is well tolerated in animals [107] ."

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"However, the commercially available inhibitors for these DUBs had no obvious influence on the SOX2 expression, including b-AP15 (the inhibitor of USP14 and UCHL5), P5091 (the inhibitor of USP7 and USP[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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P5091 inhibits USP47. 2 / 2

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"Our initial USP7 inhibitor , P5091 , is not specific to USP7 but additionally inhibits USP47 ( ubiquitin-specific peptidase 47 ) , which , among several functions , controls tumor cell proliferation ( 38,39 ) ."

34965932

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"Since the previous studies have demonstrated that P5091 also inhibits Usp47 activity , we chose other specific Usp7 inhibitors ( Usp7-IN-155 and HBX-1981856 ) to validate our results ."

30679505

P5091 activates USP47.

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"Both P02207 and P5091 target USP7 with the added function that P5091 simultaneously targets USP47 directing the cell fate towards apoptosis."

28923280

P5091 affects cell growth

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P5091 activates cell growth.

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"The small-molecule inhibitor P5091 targeting USP7 effectively suppresses the Warburg effect and cell growth in PDAC."

39707401

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"Prior studies have also shown that the USP7 inhibitors P5091 and P22077 inhibit NB cell growth through destabilization of N-Myc, independent of TP53 status, and identified direct interactions between USP7 and N-Myc [13]."

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"In doing that, USP7 inhibitor P5091 activates an apoptotic and cell growth arrest response which occurs by passing TP53 genetic loss."

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"Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment."

28418900

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"Intriguingly, the USP7 inhibitor (P5091) significantly inhibited myeloma cells’ cell growth and overcame NEK2-induced and -acquired BTZ resistance (Franqui-Machin et al., 2018)."

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P5091 inhibits cell growth.

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P5091 inhibits cell growth. 3 / 3

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"P5091 significantly inhibited cell growth of ovarian cancer, 19 oesophageal cancer 15 and colorectal cancer 20 in vitro and in vivo."

33129231

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"P5091 inhibits human MM cell growth in vivo and prolongs survival in the MM.1 S MM xenograft mouse model."

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"In MM cells, the concurrent use of the NEK2 inhibitor INH1 and P5091 markedly impedes cell growth and overcomes NEK2-related and inherent BTZ resistance by modulating the NF-κB and PP1α/AKT pathways [175]."

38702734

P5091 affects CTNNB1

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P5091 ubiquitinates CTNNB1.

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P5091 leads to the ubiquitination of CTNNB1. 3 / 3

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"As shown in Fig. 3 A, Myc-Ub transfection alone moderately increased ubiquitination of β-catenin, however, treatment of P5091 further enhanced β-catenin ubiquitination."

28216017

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"Likewise, addition of P5091 increased β-catenin ubiquitination ( Fig. 3 B and C)."

28216017

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"Compound P5091 enhances beta-catenin ubiquitination and degradation by inhibiting USP7, thereby inducing tumor apoptosis and inhibiting tumor growth."

32821165

P5091 decreases the amount of CTNNB1.

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"As shown in Fig. 4 A and B, P5091 treatment downregulated β-catenin levels in these three cell lines in a dose-dependent manner."

28216017

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"Results of cytoplasmic and nuclear fraction assays and immunofluorescence assays reflected that P5091, to some extent, reduced β-catenin level of the cytoplasm and nucleus in HCT116 and SW480 cells ( [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

28216017

P5091 inhibits CTNNB1.

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"P5091 accelerated the degradation of β-catenin in both HCT116 and SW480 cells ( Fig. 3 D–G)."

28216017

P5091 deubiquitinates CTNNB1.

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P5091 leads to the deubiquitination of CTNNB1. 1 / 1

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"P5091, a specific inhibitor of UPS7, inhibits the growth of CRC cells by promoting ubiquitination and degradation of β-catenin."

36969062

P5091 activates CTNNB1.

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P5091 activates CTNNB1. 1 / 1

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"P5091 attenuates Wnt pathway activity by promoting β-catenin degradation, which inhibits CRC cell proliferation and promotes apoptosis in vitro (214)."

36579676

USP7 affects P5091

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USP7 inhibits P5091.

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"USP7 was inhibited (P5091, Selleck #S7132, Selleck Chemicals, Houston, TX, USA) with doses ranging from 0.1 to 4 µM for 2–72 h. For measurement of growth rates, 100,000 cells were seeded in T-25 cell culture flasks and treated as indicated."

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"However, senescent p53 knockout cells were resistant to apoptosis and cell death caused by USP7 inhibition with P5091 (Figure 3a, b)."

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USP7 activates P5091.

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"Overexpression of ARF4 in cells in which USP7 was inhibited using shRNA or P5091 resulted in a significant reduction in the Q2 (Annexin V-FITC + PI+), Q3 (Annexin V-FITC + PI-) and Q2 + Q3 subpopulations compared to the group that was inhibited alone."

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"This suggests that ARF4 overexpression effectively prevented early-, late-stage apoptosis and total apoptosis induced by USP7 inhibition using shRNA or P5091."

34556124

USP7 deubiquitinates P5091.

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"Collectively, our studies utilize MM cell lines, patient tumor cells, and MM xenograft models, as well as biochemical and genetic models, to show the anti-tumor activity of a USP7 deubiquitylating enzyme inhibitor P5091."

22975377

P5091 affects Wnt

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P5091 inhibits Wnt.

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P5091 inhibits Wnt. 3 / 3

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28216017

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"P5091 attenuates Wnt pathway activity by promoting β-catenin degradation, which inhibits CRC cell proliferation and promotes apoptosis in vitro (214)."

36579676

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"These results demonstrated that P5091 has potent anti-tumor activity in vivo without clear toxicity.To determine whether Wnt signaling was also repressed by P5091 in HCT116 xenografts, extracts of tum[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

28216017

P5091 activates Wnt.

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P5091 activates Wnt. 2 / 2

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"One of the USP7 inhibitors, P5091 represses the Wnt signaling pathway by enhancing ubiquitin mediated degradation of beta-catenin in CRC cells as well as in in vivo models [XREF_BIBR]."

32486158

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"The USP7 inhibitor P5091 has been demonstrated to effectively inhibit Wnt signaling and tumor growth, underscoring the pivotal role of USP7 in this context [28]."

39707401

P5091 affects Mice

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P5091 activates Mice.

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"32 Our study here aimed to examine the effect of P5091 on antitumor immunity and its possible role in cancer immunotherapy.In our study, we found that P5091 promoted colon cancer cell apoptosis and death in CT26 xenografted mice and that the effect was similar when compared to an anti-PD-1-treated group."

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"In vivo, P5091 effectively attenuates bone loss in OVX mice."

37333461

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"Furthermore, P5091 treatment caused FOXP3 loss in Treg cells decreased the proportion of Treg cells in tumor bearing mice."

30697058

P5091 inhibits Mice.

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P5091 inhibits Mice. 2 / 2

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"As expected, mice in which USP7 activity was inhibited by P5091 showed dramatically increased susceptibility to Salmonella typhimurium."

36032091

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"Interestingly, systemic injection of P5091 abolished locomotor sensitization in control mice, similar to the effect of Maged1 inactivation (Fig. 4g, h and Supplementary Fig. 10), with no effect on spontaneous locomotor activity (Supplementary Fig. 10b), and no effect on the locomotor activity of Maged1-cKO mice (Supplementary Fig. 10c)."

38123574

P5091 affects cell death

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"Annexin V staining likewise demonstrated P5091 induced cell death in TP53 wild-type Ewing sarcoma cell lines (XREF_FIG)."

30045945

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"This suggests that, as in other malignancies, P5091 can also induce GBM cell death."

34556124

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"In addition, P5091, besides working synergistically with conventional treatment drugs, induces cell death of multiple myeloma cells that are resistant to the standard therapy."

27057639

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"The role of HDM2 during P5091 induced cell death was further examined using p53 -/- and p53 -/- / MDM2 -/- (double KO) mouse embroyonic fibroblasts (MEFs)."

22975377

P5091 affects DDX53

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P5091 activates DDX53.

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"A selective USP7 inhibitor, P5091, effectively inhibits CT26 xenograft growth in mice, similar to anti-PD-1 antibody treatment [93]."

38474186

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30697058

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"Compound P5091, a selective USP7 inhibitor, was found to inhibit CT26 xenografts growth in mice, which is comparable to the effect of Anti-PD-1 antibody."

30697058

P5091 inhibits DDX53.

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P5091 inhibits DDX53. 1 / 1

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"As shown in Figure 1A, P5091 inhibited the growth of CT26 xenografts in a dose-dependent manner, as evidenced by tumor volume and the fact that a high-dose treatment of P5091 had the same effect as anti-PD-1 treatment."

30697058

P5091 affects Ubiquitin

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P5091 inhibits Ubiquitin.

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"Moreover, P5091 inhibits USP7-, but not USP2- or USP8 mediated cleavage of poly K48 linked ubiquitin chains (visualized by the presence or absence of mono-ubiquitin) (XREF_SUPPLEMENTARY)."

22975377

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"Continuous treatment with the USP7 inhibitor P22077 or P5091 substantially reversed the accumulation of SUMOylated proteins in Rnf4 cells, presumably by stabilizing ubiquitin chains on those proteins to enable proteasomal targeting (Figure 3C)."

38530355

P5091 activates Ubiquitin.

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P5091 activates Ubiquitin. 1 / 1

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"One of the USP7 inhibitors, P5091 represses the Wnt signaling pathway by enhancing ubiquitin mediated degradation of beta-catenin in CRC cells as well as in in vivo models [XREF_BIBR]."

32486158

P5091 affects TXN

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"Treatment of mice with the USP7 inhibitor P5091 effectively eliminated SnCs and reduced the expression of SASP factors induced by DOX without affecting body weight or blood cell counts."

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"This suggestion is supported by our finding that treatment of mice with the USP7 inhibitor P5091 effectively eliminated SnCs and reduced the expression of SASP factors caused by DOX.In conclusion, we reveal that USP7 is a novel senolytic target, and USP7 inhibition can selectively kill some SnCs with p53 downregulation in vitro and clear SnCs induced by chemotherapy in mice in part by destabilizing MDM2 to increase p53 expression."

32064756

P5091 inhibits TXN.

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P5091 inhibits TXN. 1 / 1

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"Interestingly , in vivo administration of USP7 inhibitor , P5091 , successfully removes senescent cells and abrogated SASP production in DOX-treated p16Ink4a -3 MR mice ( He , et al ., 2020 ) ."

33275998

P5091 affects SAMHD1

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P5091 ubiquitinates SAMHD1.

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P5091 leads to the ubiquitination of SAMHD1. 1 / 1

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"Administration of P5091 significantly increased ubiquitination of SAMHD1 protein in HCT116 (Fig. 3C), SW480 (Fig. S1O), Hela (Fig. S1P) and HEK293 (Fig. S1Q) cells, respectively."

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P5091 increases the amount of SAMHD1.

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"P5091, a specific USP7 inhibitor, decreased SAMHD1 levels in both concentration and time dependent manners in HCT116 (Fig. 2C; Fig. S1K) and H1299 (Fig. S1J) cells, respectively."

37081042

P5091 activates SAMHD1.

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"Furthermore, the USP7 inhibitor P5091 suppresses the increase of SAMHD1 protein induced by cisplatin or doxorubicin (Fig. 4N; Fig. S5D)."

37081042

P5091 affects Reactive Oxygen Species

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"Moreover, P5091 can induce ROS production and decrease membrane potential in high glucose senescent HDF cells ( Fig. 2 D)."

38788355

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"To sum up, low-dose P5091 can selectively eliminate senescent cells, reduce the release of SASP, induce ROS production and decreased MMP in senescent HDF cells.To investigate the molecular function of[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

38788355

P5091 increases the amount of Reactive Oxygen Species.

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"Fig. 3 A reveals that both P22077 and P5091 highly induce intracellular ROS levels in several cancer cell lines."

26768359

P5091 affects IL10

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"RT-PCR analysis showed that P5091 treatment decreased IL-10 mRNA level in tumor tissue while elevated mRNA level of IFN-gamma and TNF-alpha."

30697058

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"P5091 decreased the levels of anti-inflammatory cytokine IL-10 and increased proinflammatory IFN-γ and TNF-α in tumor tissue and TME."

36428632

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"P5091 treatment promoted IFN-gamma and TNF-alpha and suppressed IL-10 expression."

30697058

P5091 affects CASP3

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"Treatment of MM.1 S and RPMI-8226 cells with P5091 induces caspase-3 cleavage, as well as activates caspase-9 and casapse-8 apoptotic pathways (XREF_SUPPLEMENTARY)."

22975377

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"Further, P5091 treatment also triggered cleavage of PARP and caspase-3 in a dose-dependent manner (Figure 2D)."

30697058

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"As shown in Fig. 6 D–G, exposure of HCT116, SW480 and Caco-2 cells with P5091 induced caspase-3 cleavage and activated the caspase-8 and caspase-9 apoptotic pathways, associated with the cleavage of p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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P5091 affects CASC3

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"Through high-throughput screening, scientists identified another novel USP7 inhibitor, the thiophenyl compound P5091, which induces apoptosis in BTZ-resistant MM cells."

38702734

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"The combination treatment with P5091 significantly reversed the BTZ resistance in MM cells with high levels of CRIP1 (Fig. 7b and c)."

38199044

P5091 affects AKT

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P5091 inhibits AKT.

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P5091 inhibits AKT. 2 / 2

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"Furthermore, USP7 inhibitor P5091 inhibited HB development and PI3K and AKT pathway."

33780361

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"Therefore, USP7 inhibitor P5091 can simultaneously both activate pro apoptotic via FOXO mediated oxidative stress and inactivate pro survival PI3K and Akt pathways."

27118403

P5091 decreases the amount of AKT.

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"Furthermore, P5091 downregulated the phosphorylation levels of AKT, HK2 and c‐Abl (Figure 8D), which was consistent with previous findings."

38082439

P5091 affects inflammatory response

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P5091 inhibits inflammatory response.

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"In this study, USP7 depletion and P5091 were shown to inhibit inflammation in senescent bone marrow-derived macrophages (BMDMs) and promote osteogenic differentiation in aged bone marrow mesenchymal stromal cells (BMSCs)."

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P5091 activates inflammatory response.

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"Although NRF2 overactivation can also exacerbate colitis, 57 we found that the USP7 inhibitor P5091 relieved oxidative stress and attenuated gut inflammation in a DSS‐induced colitis mouse model, suggesting the clinical translation of USP7 inhibitors for IBD treatment."

39887666

P5091 affects cellular senescence

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"Overall, these cell experimental data explained the biological mechanism by which P5091 selectively induced senescence HDF cell apoptosis by activating the p53 signaling pathway, which has clinical va[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

38788355

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"As shown in Fig. 2 D, the P5091 led to a significant increase in ROS generation in senescence cells compared with NTC."

38788355

P5091 affects cell differentiation

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P5091 inhibits cell differentiation.

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P5091 activates cell differentiation.

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"The USP7 selective small-molecule inhibitors P5091 and P22077 inhibited cell proliferation and induced megakaryocytic differentiation in both cell lines and primary cells."

32130729

P5091 affects bortezomib

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P5091 inhibits bortezomib.

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25444757

P5091 activates bortezomib.

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P5091 activates bortezomib. 1 / 1

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"To determine whether P5091 similarly affects purified patient MM cells, tumor cells from 8 MM patients, including those relapsing after multiple prior therapies such as bortezomib, lenalidomide, and Dex, were treated with P5091."

22975377

P5091 affects USP22

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P5091 activates USP22. 2 / 2

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"By Western blot analysis, we showed that MDM2 was slightly decreased in both parental and USP22-Ko A549 cancer cells, while USP22 was significantly upregulated by P5091 treatment (Fig. 6D), which confirms that P5091 effectively inhibited USP7 deubiquitinase activity."

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"In the study, we found that USP7 inhibition by three inhibitors: HBX4418 [45], P5091 [41], and FT671 [12] dramatically upregulates USP22 in cancer cells through transcriptional mechanisms, and given the critical role of USP22 in carcinogenesis and anticancer response, we propose that the upregulated USP22 may represent a critical side-effects of USP7 inhibition.We further examined the expression and activation of downstream signaling of USP22 pathway by USP7 inhibition and found that this feedback upregulation has a significant impact on USP22 pathway and USP22-related oncogenes."

37946202

P5091 affects SRSF6

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P5091 increases the amount of SRSF6.

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P5091 decreases the amount of SRSF6.

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32444465

P5091 affects PI3K

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P5091 inhibits PI3K. 2 / 2

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"Furthermore, USP7 inhibitor P5091 inhibited HB development and PI3K and AKT pathway."

33780361

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"Therefore, USP7 inhibitor P5091 can simultaneously both activate pro apoptotic via FOXO mediated oxidative stress and inactivate pro survival PI3K and Akt pathways."

27118403

P5091 affects Melanoma

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P5091 inhibits Melanoma.

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"P5091 treatment inhibited melanoma tumor growth Figure 7 F)."

36130505

P5091 activates Melanoma.

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"Moreover, P5091 induces melanoma cell senescence and sensitizes cells to HDAC/LSD1 inhibitors [55]."

39707401

P5091 affects KDR

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P5091 inhibits KDR.

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"P5091 decreases the number of VEGFR2- and PECAM1 positive cells (XREF_FIG)."

22975377

P5091 dephosphorylates KDR.

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"In HUVECs pretreated with ACEI, P22077 and P5091 inhibited the VEGF-induced phosphorylation of VEGFR2, PLCγ, and ERK1/2 considerably (Fig. S13B)."

36759621

P5091 affects HMBS

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P5091 inhibits HMBS.

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"We also used two inhibitors targeting non proteasomal UPS components : PYR-41, an inhibitor of ubiquitin E1 ligase and several DUBs, and P5091, a specific USP7 and USP47 inhibitor 32."

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P5091 activates HMBS.

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"Given that P5091, like bortezomib, targets the UPS, we examined whether P5091 similarly enhances the anti-MM activity of other agents."

22975377

P5091 affects HK2

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"In contrast, P5091 decreased HK2 expression and inhibited the production of lactate and pyruvate in NSCLC cells (Figure 7H,I)."

38082439

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"Furthermore, P5091 downregulated the phosphorylation levels of AKT, HK2 and c‐Abl (Figure 8D), which was consistent with previous findings."

38082439

P5091 affects H2AX

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"P5091 and domatinostat combination induced p53 activation and increased γH2AX expression, suggesting DNA damage as a putative trigger of apoptosis ( Figure 7 L)."

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No evidence text available

35821281

P5091 affects FOXP3

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P5091 inhibits FOXP3.

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"P5091 treatment inhibited FOXP3 + Treg function in the tumor microenvironment."

30697058

P5091 decreases the amount of FOXP3.

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"Furthermore, P5091 also inhibited FOXP3 expression in CD4 T-cells, indicating an impaired immune tolerance in the tumor microenvironment."

30697058

P5091 affects EZH2

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P5091 increases the amount of EZH2.

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"In contrast, USP7-knockdown and P5091 treatment reduced the protein levels of all the EZH2 GOF mutants."

32453339

P5091 activates EZH2.

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P5091 activates EZH2. 1 / 1

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"Thus, treatment with USP7 inhibitor P5091 promoted EZH2 destabilization, similar to the effect observed after USP7-knockdown."

32453339

P5091 affects Colitis

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"Notably, the USP7 inhibitor, P5091, inhibits oxidative stress and colitis in vivo."

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"As shown in Figure 6B–D, P5091‐treated mice with DSS‐induced colitis presented with alleviated colitis, which manifested as longer colon length, lower spleen weight, and lower disease activity index (DAI) scores than those treated with PBS."

39887666

P5091 affects Cell Survival

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P5091 inhibits Cell Survival. 2 / 2

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"The combination of P5091 and BTZ efficiently decreased the cell viability."

38199044

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"The USP5 inhibitor WP1130 and mebendazole, the USP7 inhibitor P5091, the Otub1 inhibitor lanatoside C, nanchangmycin, and acevaltrate all promote c-Maf degradation and suppress MM cell survival [ 14 ][MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

36564282

P5091 affects ANGPTL1

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"MM.1 S, ARP-1, and RPMI-8226 cells were treated with RRx-001 and P5091 across a range of concentrations."

27118403

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"Since our in vitro data showed that P5091 triggers apoptosis in p53-null ARP-1 MM cells, we evaluated whether P5091 similarly affects the growth of ARP-1 cells in vivo."

22975377

Pan affects P5091

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Pan inhibits P5091. 1 / 1

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"Further, the pan‐caspase inhibitor QVD abrogated the effect of P5091 on the viability of SnCs (Figure 2e)."

32064756

USP7 inhibitor affects P5091

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USP7 inhibitor activates P5091. 1 / 1

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"Collectively, these results demonstrate that the USP7 inhibitor P5091 inhibits oxidative stress and attenuates DSS‐induced colitis in vivo.We further explored the protective effects of P5091 on intestinal barrier integrity during intestinal inflammation."

39887666

P5091 affects Φ

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"The packaging of P5091 did not affect the targeting properties of P5091@RMPs‐R4F compared with RMPs‐R4F.To determine whether the loading of P5091 in P5091@RMPs‐R4F could enhance the M2Φ polarization ability of RMPs, we used CD206 and CD86 as representative markers of the polarization of MΦ to identify the reprogramming ability of the tested groups."

36698296

P5091 affects ubiquitinated HDM2

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P5091 inhibits ubiquitinated HDM2. 1 / 1

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eidos

"P5091 increases ubiquitinated HDM2 , which is then degraded and leads to p53-mediated cytotoxicity in cancer cells [ 108 ] ."

| PMC

P5091 affects ubiquitin C-term tail

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P5091 inhibits ubiquitin C-term tail. 1 / 1

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"Hence , P5091 acquired this space and perform its inhibition mechanism where it blocks the ubiquitin C-term tail ( Figure 7F ) ."

30344943

P5091 affects tumour growth

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P5091 inhibits tumour growth. 1 / 1

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"In multiple myeloma cells , P5091 stabilized p53 and inhibited tumour growth , whereas in animal models , P5091 was well tolerated , inhibited tumour growth and prolonged survival99 ."

28959952

P5091 affects tumor growth

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P5091 inhibits tumor growth. 1 / 1

| 1

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eidos

"In addition , P5091 inhibits tumor growth and synergizes with other chemotherapeutic agents such as lenalidomide , HDAC inhibitor or dexamethasone to induce synergistic anti-multiple myeloma effect [ 32 , 33 ] ."

32002017

P5091 affects transcriptional regulator

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P5091 increases the amount of transcriptional regulator. 1 / 1

| 1

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38788355

P5091 affects terbufos

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P5091 inhibits terbufos. 1 / 1

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"For example, in the case of ATSP-7041 and P5091 treatment, the addition of P5091 suppresses the counter up-regulation of MDM2."

30045945

P5091 affects tellurium atom

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| 1

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"Our results showed that RNAi-mediated silencing of USP7 in mouse embryos or treatment with P5091, a small molecule inhibitor of USP7, significantly reduced blastocyst rate and blastocyst quality, and decreased total and TE cell numbers per blastocyst, as well as destroying normal lineage differentiation."

38438135

P5091 affects tat

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| 1

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"Cells were transfected with both 89.6 and the Flag-Tat vector and then treated with F07#13 (1 µM) for 48 h. Twenty-four hours post F07#13 treatment, cells were treated with MG132 (10 ng/mL) or P5091 (3 µM) and incubated for 24 h. Results in Fig. 1c show that Tat levels were decreased with F07#13; however, addition of P5091 greatly reduced Tat levels."

31036006

P5091 affects target

| 1

P5091 inhibits target. 1 / 1

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"We validated these results via RT-qPCR and found that P5091 indeed decreased Yap target genes expression , without affecting yap mRNA level ( Fig. 7i ) ."

30679505

P5091 affects synergistic anti-multiple myeloma

| 1

P5091 activates synergistic anti-multiple myeloma. 1 / 1

| 1

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eidos

"In addition , P5091 inhibits tumor growth and synergizes with other chemotherapeutic agents such as lenalidomide , HDAC inhibitor or dexamethasone to induce synergistic anti-multiple myeloma effect [ 32 , 33 ] ."

32002017

P5091 affects sensitization

| 1

P5091 inhibits sensitization. 1 / 1

| 1

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38123574

P5091 affects sensitivity bortezomib-resistant cancer cells

| 1

P5091 activates sensitivity bortezomib-resistant cancer cells. 1 / 1

| 1

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eidos

"P5091 restores sensitivity to bortezomib-resistant cancer cells , and shows synergistic effects when combined with proteasome and histone deacetylase ( HDAC ) inhibitors [ 108 ] ."

| PMC

P5091 affects proteasome inhibitor

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P5091 activates proteasome inhibitor. 1 / 1

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25444757

P5091 affects pdaC

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P5091 activates pdaC. 1 / 1

| 1

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"The small-molecule inhibitor P5091 targeting USP7 effectively suppresses the Warburg effect and cell growth in PDAC."

39707401

P5091 affects osteoclast differentiation

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P5091 inhibits osteoclast differentiation. 1 / 1

| 1

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"Osteoclast differentiation could be significantly inhibited by siRNA or a specific inhibitor (P5091)."

37333461

P5091 affects ossification

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"Tang et al. reported a similar case, where HBX41108 and P5091 inhibited osteogenesis, which also provided a potential therapeutic approach for hyperplasia of bone formation, however, resulted in the side effect of osteoporosis [52]."

37199589

P5091 affects necrosis

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"P5091 effectively suppressed the growth of ovarian cancer cells, caused cell cycle blockage, and induced necrosis and apoptosis with more severe phenotypes observed in HeyA8 cells with wild-type p53 than in OVCAR-8 cells with mutant p53."

29049989

P5091 affects lenalidomide

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P5091 activates lenalidomide. 1 / 1

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22975377

P5091 affects homeostatic process

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P5091 inhibits homeostatic process. 1 / 1

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"The selective inhibitor of USP7, P5091, has also been found to promote bone repair and homeostasis in osteoporotic conditions."

39651622

P5091 affects gene expression

| 1

P5091 activates gene expression. 1 / 1

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"Similarly, in 2i treated group, P5091 application caused a significant decrease in C-MYC, KLF4, AXIN, and β-Catenin gene expression levels by 10-fold, 38-fold, 4.3-fold, and 2.5-fold, respectively."

37533669

P5091 affects cisplatin

| 1

P5091 inhibits cisplatin. 1 / 1

| 1

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"Consistently, in vitro (Fig. 7e, f and Supplementary Fig. 10c–e) and in vivo (Fig. 7g, h) assays showed that USP7 inhibitor P5091 enhanced the antitumor effect of cisplatin in NPC, and this process was enhanced after knockdown of TOP2A."

38287116

P5091 affects cell

| 1

P5091 inhibits cell. 1 / 1

| 1

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eidos

"We chose another HCC cell line to confirm this result , and found that P5091 also inhibited 7721 cell proliferation in a dose-related manner ( Supplementary Fig. 7c ) ."

30679505

P5091 affects cell growth ovarian cancer oesophageal cancer colorectal cancer

| 1

P5091 inhibits cell growth ovarian cancer oesophageal cancer colorectal cancer. 1 / 1

| 1

➶

eidos

"P5091 significantly inhibited cell growth of ovarian cancer , 19 oesophageal cancer 15 and colorectal cancer 20 in vitro and in vivo ."

33129231

P5091 affects cell cycle

| 1

P5091 inhibits cell cycle. 1 / 1

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29049989

P5091 affects cell apoptosis

| 1

P5091 activates cell apoptosis. 1 / 1

| 1

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eidos

"P5091 triggers cell apoptosis in multiple myeloma cells and overcomes bortezomib resistance by inhibiting HAUSP activity53 ."

30679505

P5091 affects c-PARP1

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P5091 increases the amount of c-PARP1. 1 / 1

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38788355

P5091 affects apoptosis myeloma

| 1

P5091 activates apoptosis myeloma. 1 / 1

| 1

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eidos

"P5091 can induce the apoptosis of multiple myeloma ( MM ) cells resistant to traditional therapy or bortezomib by inhibiting the activity of USP7 , and can also play a synergistic role when used in combination with dexamethasone or lenalidomide ."

33925279

P5091 affects apoptosis lymphoma

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P5091 activates apoptosis lymphoma. 1 / 1

| 1

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eidos

"For each cells , values without common letters ( a , b , c ) in the superscript differ statistically ( P < .05 ) Inhibiting USP7 triggers DNA damage in canine lymphoma / leukemia cell lines After establishing that P5091 triggers apoptosis in lymphoma / leukemia cells , we examined if the induced apoptosis resulted from DNA damage ."

33650720

P5091 affects anti-PD-1 antibody

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P5091 activates anti-PD-1 antibody. 1 / 1

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"A selective USP7 inhibitor, P5091, effectively inhibits CT26 xenograft growth in mice, similar to anti-PD-1 antibody treatment [93]."

38474186

P5091 affects aging

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P5091 inhibits aging. 1 / 1

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"While knockdown of USP7 and treatment with small molecule inhibitors P5091 or C646 could effectively reduce the expression of these aging genes ( Fig. 7 H, I)."

35114313

P5091 affects Wnt/β-catenin

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P5091 inhibits Wnt/β-catenin. 1 / 1

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"Results in Fig. 2 B show that P5091 treatment could impede the ST-Luc activity stimulated by Wnt1 transfection.We then assessed whether P5091 inhibited the activity of Wnt/β-catenin signaling in color[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

28216017

P5091 affects WNT1

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P5091 activates WNT1. 1 / 1

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"It demonstrated that in Usp7 RNAi worms, the tail-less regeneration phenotype was regulated by the Islet/Wnt1 axis.In addition, it was reported that USP7 is a tumor-specific Wnt activator that mediates the treatment of APC-mutated colorectal cancer [38], and the USP7 inhibitor P5091 attenuated wnt1 activity in the Wnt signaling pathway and inhibited the growth of colorectal cancer [39]."

39885534

P5091 affects USP7 myeloma

| 1

P5091 inhibits USP7 myeloma. 1 / 1

| 1

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eidos

"P5091 is shown to selectively inhibit USP7 in multiple myeloma both in vitro and in vivo [ 213 ] ."

33805973

P5091 affects USP14

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P5091 inhibits USP14. 1 / 1

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31605775

P5091 affects USP10

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P5091 inhibits USP10. 1 / 1

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"These compounds were found to be highly selective for USP7 in counter-screening against a panel of DUBs including USP10 and USP47, which are also inhibited by P5091."

30486612

P5091 affects UCHL5

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31605775

P5091 affects Tumor Microenvironment

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P5091 inhibits Tumor Microenvironment. 1 / 1

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"P5091 treatment inhibited FOXP3 + Treg function in the tumor microenvironment."

30697058

P5091 affects TYRP1

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P5091 decreases the amount of TYRP1. 1 / 1

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"In the present study, P5091 treatment dramatically decreased the induction of NF-κB protein expression by PCN, providing additional evidence that USP7 controls airway mucus secretion via NF-κB. Notably, deubiquitination was not used in this study when attempting to regulate NF-κB via USP7."

38778971

P5091 affects TNFSF11

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P5091 increases the amount of TNFSF11. 1 / 1

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"Treatment with the USP7 inhibitor P5091 not only almost completely eliminated SnCs but also abrogated DOX‐induced increase in the levels of Il1α, Il1β, Il6, and Tnfsf11 mRNAs (Figure 4d)."

32064756

P5091 affects TNF

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P5091 increases the amount of TNF. 1 / 1

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"In addition, P5091 treatment suppressed IL-10 and promoted IFN-γ and TNF-α expression, both at the mRNA and protein levels."

30697058

P5091 affects TGFB

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"Furthermore, P5091 treatment was found to significantly reduce the mRNA levels of IL1A , IL1B , TGF-β , and MMP1 in senescent HDF cells ( Fig. 2 C)."

38788355

P5091 affects TAT

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"DUB and USP7 specific inhibitors, PR-619 and P5091, were shown to cause degradation of TAT and ultimately led to a decrease in virus production."

32603670

P5091 affects Small t antigen

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P5091 inhibits Small t antigen. 1 / 1

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28216017

P5091 affects Sarcoma

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P5091 activates Sarcoma. 1 / 1

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"The USP7 inhibitor P5091 inhibits Ewing’s sarcoma growth and extends survival time by combined with other treatments [19]."

32002017

P5091 affects Santa

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P5091 activates Santa. 1 / 1

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"LLC and anti p53 (Do-7, sc47698), Santa Cruz Biotechnology, were utilized.H526 and H209 cells were treated with P5091 at 12.5 muM for 24 h and apoptosis was quantified by measuring Caspase 3/7 activat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

27372520

P5091 affects STING1

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P5091 activates STING1. 1 / 1

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"Moreover, P5091 impaired USP7-mediated protection of STING degradation (Fig. 4I), occurring an enhanced ubiquitination of STING, for its subsequent degradation (Fig. 4J)."

37199589

P5091 affects STAT5

| 1

P5091 leads to the dephosphorylation of STAT5. 1 / 1

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"As shown in Fig. 5B, P5091 significantly decreased STAT5, Lyn and CRKL phosphorylation."

33963175

P5091 affects SOCS1

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P5091 increases the amount of SOCS1. 1 / 1

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"Importantly, USP7 small-molecule inhibitors, P5091 and P22077, inhibit SOCS1 expression and enhance IFN-I antiviral efficacy."

31691271

P5091 affects SNAI1

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"Interestingly, treatment with a pharmacological inhibitor targeting USP47 (P5091) upregulated E-cadherin and downregulated SNAIL both in the nucleus and cytoplasm, while reducing morphological changes otherwise observed in MCF10A cells treated with TGF-β2 [78]."

38067168

P5091 affects SLC2A1

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"In addition, we found that small molecule inhibitors P5091 of USP7 or p300 could also effectively block the inhibitory effect of CSE on cell proliferation ( Fig. 6 C)."

35114313

P5091 affects SHH

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P5091 decreases the amount of SHH. 1 / 1

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"Furthermore, we revealed that both P5091 and P22077 treatment inhibited the expression of Shh pathway target genes, such as gli1 , hhip1 , ptch1 and bcl2 ( Fig. 4 C)."

28137592

P5091 affects RMPs

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36698296

P5091 affects Parkinson Disease

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P5091 activates Parkinson Disease. 1 / 1

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"In conclusion, compared with P5091 and RMPs‐R4F alone, P5091@RMPs‐R4F demonstrates an effective therapeutic effect on BRM.As PD‐1 antibody therapy has shown potential to treat lung metastases, and we found that P5091 treatment could enhance PD‐L1 expression, 22 we hypothesized that P5091@RMPs‐R4F combined with PD‐1 antibody therapy could achieve greater efficacy."

36698296

P5091 affects PTEN

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"It was also reported that USP7 inhibition (P5091) restores PTEN nuclear pool and its onto suppressive activity in chronic lymphocytic leukemia (Carrà et al., 2017)."

33967786

P5091 affects PPP1

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P5091 inhibits PPP1. 1 / 1

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38702734

P5091 affects PMAIP1

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P5091 activates PMAIP1. 1 / 1

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"Additionally, P5091 treatment was found to enhance the mRNA levels of apoptosis-related genes BAX and NOXA in senescent HDF cells compared to control ( Fig. 3 H), confirming the induction of apoptosis[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

38788355

P5091 affects PECAM1

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P5091 inhibits PECAM1. 1 / 1

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"P5091 decreases the number of VEGFR2- and PECAM1 positive cells (XREF_FIG)."

22975377

P5091 affects PARP1

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"Further, P5091 treatment also triggered cleavage of PARP and caspase-3 in a dose-dependent manner (Figure 2D)."

30697058

P5091 affects PARP inhibitors

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P5091 inhibits PARP inhibitors. 1 / 1

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"One USP7 inhibitor, P5091, regulated CCDC6 degradation and enhanced cell sensitivity to PARP inhibitors."

37215134

P5091 affects Nftac1

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"Furthermore, following RANKL-induced stimulation, the expression of Nftac1, c-fos, Ctsk, and Atp0d2 was enhanced by P5091 treatment (Supplementary Fig. 5)."

37199589

P5091 affects Neuroblastoma

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P5091 inhibits Neuroblastoma. 1 / 1

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31282934

P5091 affects Neoplasm Metastasis

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P5091 inhibits Neoplasm Metastasis. 1 / 1

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"Interestingly, both P5091 and P22077 treatment apparently blocked Daoy cell proliferation and metastasis ( Fig. 4 A and B)."

28137592

P5091 affects Neoplasm Invasiveness

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P5091 inhibits Neoplasm Invasiveness. 1 / 1

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"When evaluated in mice with Lewis lung carcinoma, USP7 inhibitor P5091 slowed tumor growth and promoted the infiltration of M1 macrophages and IFN-γ-expressing CD8+ T cells."

36428632

P5091 affects NQO1

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P5091 leads to the deubiquitination of NQO1. 1 / 1

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"Our in vitro assays revealed that P5091 significantly enhanced the interaction between DUB3 and NRF2 and inhibited K48‐linked NRF2 ubiquitination, resulting in increased expression of NRF2, HO‐1, and NQO1 in P5091‐treated HT29 cells (Figure S5D–F, Supporting Information)."

39887666

P5091 affects NPC

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P5091 inhibits NPC. 1 / 1

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38287116

P5091 affects NFE2L2

| 1

P5091 leads to the deubiquitination of NFE2L2. 1 / 1

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39887666

P5091 affects NEK2

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P5091 inhibits NEK2. 1 / 1

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"It has recently been revealed that P5091, a nonreversible USP7 inhibitor, can deplete NEK2 protein in vitro and in vivo, resulting in suppression of NEK2 downstream target, thus overcoming bortezomib resistance."

33520703

P5091 affects NEK2 protein

| 1

P5091 inhibits NEK2 protein. 1 / 1

| 1

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"It has recently been revealed that P5091 , a nonreversible USP7 inhibitor , can deplete NEK2 protein in vitro and in vivo , resulting in suppression of NEK2 downstream target , thus overcoming bortezomib resistance ( 98 ) ."

33520703

P5091 affects NEK2 downstream target

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P5091 inhibits NEK2 downstream target. 1 / 1

| 1

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"It has recently been revealed that P5091 , a nonreversible USP7 inhibitor , can deplete NEK2 protein in vitro and in vivo , resulting in suppression of NEK2 downstream target , thus overcoming bortezomib resistance ( 98 ) ."

33520703

P5091 affects Medulloblastoma

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P5091 inhibits Medulloblastoma. 1 / 1

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"To assess whether Usp7 inhibitors block MB cell proliferation and migration, we treated the cells with P5091 or P22077 at corresponding concentrations as previously described [19,20] ."

28137592

P5091 affects MYC

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P5091 decreases the amount of MYC. 1 / 1

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"Furthermore, immunohistochemical analysis revealed that c-Myc protein level in ductal cancer cells was markedly decreased by P5091 treatment (Fig. 6C, D)."

39707401

P5091 affects MMP1

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P5091 decreases the amount of MMP1. 1 / 1

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"Furthermore, P5091 treatment was found to significantly reduce the mRNA levels of IL1A , IL1B , TGF-β , and MMP1 in senescent HDF cells ( Fig. 2 C)."

38788355

P5091 affects MAF

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36564282

P5091 affects LYN

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P5091 leads to the dephosphorylation of LYN. 1 / 1

| 1

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"As shown in Fig. 5B, P5091 significantly decreased STAT5, Lyn and CRKL phosphorylation."

33963175

P5091 affects KPNB1

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"Consistently, P5091 also accelerated the degradation of KPNB1 (Fig. 7I and J)."

38254206

P5091 affects KDM5B

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P5091 activates KDM5B. 1 / 1

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"We further showed that the USP7 inhibitor, P5091, enhanced the sensitivity of NPC cells to cisplatin by inducing KDM5B degradation, which provides a potential therapeutic strategy for inhibiting the KDM5B/ZBTB16/TOP2A axis in NPC."

38287116

P5091 affects IL6

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"Treatment with the USP7 inhibitor P5091 not only almost completely eliminated SnCs but also abrogated DOX‐induced increase in the levels of Il1α, Il1β, Il6, and Tnfsf11 mRNAs (Figure 4d)."

32064756

P5091 affects IL1B

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"Furthermore, P5091 treatment was found to significantly reduce the mRNA levels of IL1A , IL1B , TGF-β , and MMP1 in senescent HDF cells ( Fig. 2 C)."

38788355

P5091 affects IL1A

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P5091 decreases the amount of IL1A. 1 / 1

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"Furthermore, P5091 treatment was found to significantly reduce the mRNA levels of IL1A , IL1B , TGF-β , and MMP1 in senescent HDF cells ( Fig. 2 C)."

38788355

P5091 affects IL1

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P5091 increases the amount of IL1. 1 / 1

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"Treatment with the USP7 inhibitor P5091 not only almost completely eliminated SnCs but also abrogated DOX‐induced increase in the levels of Il1α, Il1β, Il6, and Tnfsf11 mRNAs (Figure 4d)."

32064756

P5091 affects IFNG

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"In addition, P5091 treatment suppressed IL-10 and promoted IFN-γ and TNF-α expression, both at the mRNA and protein levels."

30697058

P5091 affects IC50 = 19.7 muM vs 9.2 muM

| 1

P5091 activates IC50 = 19.7 muM vs 9.2 muM. 1 / 1

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"The addition of P5091 enhanced the sensitivity to PARP-inhibitor olaparib in PC3 cells [PC3 : IC50 = 15.4 muM vs 2.01 muM in presence of 2.5 muM P5091] and in the LNCaP cells [IC50 = 19.7 muM vs 9.2 muM, in presence of 2.5 muM P5091, (in absence of DHT); IC50 = 23.9 muM vs 11.8 muM, in presence of 2.5 muM P5091 (in presence of DHT])."

28415632

P5091 affects Huh7 cell

| 1

P5091 inhibits Huh7 cell. 1 / 1

| 1

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"Furthermore , we carried out MTT experiments and found that P5091 attenuated Huh7 cell proliferation in a dose-dependent manner ( Fig. 7j ) ."

30679505

P5091 affects HMOX1

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P5091 decreases the amount of HMOX1. 1 / 1

1 |

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ctd

No evidence text available

35821281

P5091 affects HDM2/p53/p21

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"For example, P5091, a small-molecule inhibitor of USP7, activates HDM2/p53/p21 signaling axis and exerts cytotoxicity in several multiple myeloma (MM) cell models, supporting future clinical investigations of USP7 inhibitors for the treatment of malignant hematological diseases 21."

29335437

P5091 affects HDF

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38788355

P5091 affects HCT166

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"P5091 inhibited HCT166 proliferation [86] , whereas P22077 downregulated the USP7 targets MDM2, claspin, and Checkpoint kinase 1 (Chk1) and inhibited neuroblastoma growth [75] ."

33157193

P5091 affects H3K4Me3

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"45 , 46 Notably, H2Bub and H3K4me3 were significantly induced by P5091 and WP1130, leading to increased cyclin A1 expression (Figure 5A)."

33738896

P5091 affects H2Bub

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"45 , 46 Notably, H2Bub and H3K4me3 were significantly induced by P5091 and WP1130, leading to increased cyclin A1 expression (Figure 5A)."

33738896

P5091 affects G3BP2

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"Consistently, MG132, a proteasome inhibitor, blocked P5091-induced G3BP2 decrease in both cell lines (Fig. 2L)."

36878903

P5091 affects Fig. 6A-C

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"Of note, P5091 treatment did significantly suppress the in vivo growth of USP22-Ko A549 xenografts (Fig. 6A-C)."

37946202

P5091 affects FOS

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"Furthermore, following RANKL-induced stimulation, the expression of Nftac1, c-fos, Ctsk, and Atp0d2 was enhanced by P5091 treatment (Supplementary Fig. 5)."

37199589

P5091 affects FGL1

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"P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8 + T cell activity."

38589688

P5091 affects FBXO7

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"Furthermore, treatment with the USP7 inhibitor P5091 considerably suppressed the upregulation of FBXO7 (Fig 3F)."

37874827

P5091 affects Diabetes Mellitus

| 1

P5091 activates Diabetes Mellitus. 1 / 1

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"These findings suggest that P5091 expedites wound re-epithelialization, facilitates the transition from the inflammatory phase to the proliferative phase, and ultimately accelerates wound healing in D[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

38788355

P5091 affects Death

| 1

P5091 activates Death. 1 / 1

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30697058

P5091 affects DNMT1

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P5091 inhibits DNMT1. 1 / 1

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"Importantly, combined RRx-001 and P5091 triggered greater DNMT1 inhibition than either agent alone (XREF_FIG)."

27118403

P5091 affects DNA damage response, signal transduction by p53 class mediator

| 1

P5091 activates DNA damage response, signal transduction by p53 class mediator. 1 / 1

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38788355

P5091 affects Cyclin

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P5091 increases the amount of Cyclin. 1 / 1

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"Taken together, these findings indicate that the DUB inhibitors P5091 and WP1130 can reverse cyclin A1 expression and induce cell‐cycle re‐entry in PI‐tolerant cells.We further investigated whether cell‐cycle re‐entry induced by DUB inhibitors could reverse cell sensitivity and therefore have a therapeutic potency in PI‐tolerant cells."

33738896

P5091 affects Colorectal Neoplasms

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P5091 inhibits Colorectal Neoplasms. 1 / 1

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"P5091 has also been reported to inhibit colorectal tumor growth in an HCT116 xenograft mouse model by suppressing proliferation and inducing apoptosis in CRC cells [221]."

40133964

P5091 affects CTSK

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P5091 increases the amount of CTSK. 1 / 1

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"Furthermore, following RANKL-induced stimulation, the expression of Nftac1, c-fos, Ctsk, and Atp0d2 was enhanced by P5091 treatment (Supplementary Fig. 5)."

37199589

P5091 affects CRKL

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P5091 leads to the dephosphorylation of CRKL. 1 / 1

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"As shown in Fig. 5B, P5091 significantly decreased STAT5, Lyn and CRKL phosphorylation."

33963175

P5091 affects CGAS

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P5091 leads to the deubiquitination of CGAS. 1 / 1

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"Knockdown of USP7 or P5091 treatment enhanced the ubiquitination of cGAS WT, while cGAS R127K remained constant in H1299 cells ( Fig. 3 G and H)."

38331088

P5091 affects CDC20

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P5091 increases the amount of CDC20. 1 / 1

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"P5091 accelerated the degradation of AR and V7 isoform affecting PSA, UBE2C, CDC20 transcription and PC cells proliferation."

28415632

P5091 affects CD8

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P5091 inhibits CD8. 1 / 1

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"For instance, P5091 is able to downregulate FGL1, a major ligand of LAG3, thus enhancing CD8 T cell activity [54]."

39707401

P5091 affects CD274

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P5091 increases the amount of CD274. 1 / 1

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"Finally, it is noteworthy that P5091-mediated USP7 inhibition resulted in increased PD-L1 expression in tumor cells."

36428632

P5091 affects BAX

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P5091 activates BAX. 1 / 1

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38788355

P5091 affects Atp0d2

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P5091 increases the amount of Atp0d2. 1 / 1

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"Furthermore, following RANKL-induced stimulation, the expression of Nftac1, c-fos, Ctsk, and Atp0d2 was enhanced by P5091 treatment (Supplementary Fig. 5)."

37199589

P5091 affects Aging

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P5091 activates Aging. 1 / 1

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"Moreover, P5091 induces melanoma cell senescence and sensitizes cells to HDAC/LSD1 inhibitors [55]."

39707401

P5091 affects AXIN

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P5091 activates AXIN. 1 / 1

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37533669

N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal affects P5091

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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal activates P5091. 1 / 1

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"In addition, proteasome inhibitor MG132 reversed the inhibitory effect of P5091 on ERβ protein level, suggesting that USP7 upregulates ERβ protein via suppressing proteasomal degradation ( Fig. 6 E)."

38097136

GSK3 affects P5091

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GSK3 inhibits P5091. 1 / 1

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"Obtained results were found to correlate positively with the dual inhibitory groups; the expression levels of pluripotency related genes as well as GSK3β and β-catenin expression were found to decrease dramatically due to P5091 treatment.The effect of USP7 inhibition on pluripotency maintenance was further examined by half-life determination of pluripotency related proteins."

37533669

CTNNB1 affects P5091

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CTNNB1 inhibits P5091. 1 / 1

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37533669

ARF4 affects P5091

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ARF4 activates P5091. 1 / 1

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"The results showed that K48-ubiquitination of ARF4 increased after induction with P5091 or shRNA, whereas K63-ubiquitination did not change significantly (Fig. 5G, H)."

34556124