IndraLab
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MDM2 binds TP53. 1000 / 20322
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sparser
"Nutlin is a selective small-molecule inhibitor of the p53-Mdm2 interaction that releases p53 from Mdm2 control, leading to accumulation of the tumour suppressor protein and activation of the P53 pathway. xref , xref Treatment of cancer cells with wild-type P53 induces cell arrest and apoptosis in vitro and suppresses the growth of human tumour xenografts in nude mice. xref , xref "
sparser
"Considering the mode of interaction of
p53 with MDM2, constituted
by a hot spot of three critical residues, namely, Trp23, Leu26, and
Phe19, a synthetic molecule displaying three hydrophobic groups in
an orientation that mimics these residues could occupy the MDM2 cleft
and thereby inhibit the p53-MDM2 binding."
sparser
"These interac-
tions are believed to constitute core modules that act to keep in check the activity of potent transcription factors (p53 is a tumor suppressor; NF-B is a central mediator of inflammatory and immune responses.)
Can the transcriptional delay drive oscillations in the p53-Mdm2 and NFB-IB␣ feedback systems?"
sparser
"In GBM
cells, both molecules caused mitochondrial membrane potential (Δψm)
dissipation and cell viability inhibition, with higher potency compared
to the single target reference standards (PK11195 for TSPO and nutlin-3
for p53-MDM2) xref singularly applied, due
to the synergism resulting from the simultaneous modulation of both
targets."
sparser
"Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination, indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway."
sparser
"Next, we evaluated the effects of two small molecule antagonists of MDM2: nutlin, which binds to the N-terminal region of MDM2 and blocks the primary site of the MDM2–p53 interaction ( xref F; xref ), and MEL23 (MDM2 E3 ligase inhibitor 23), which blocks the E3 ligase activity of the MDM2–MDMX complex ( xref I; xref )."
sparser
"As nutlin functions to block the p53–MDM2 interaction, it would not necessarily be capable of inhibiting p53-independent functions of MDM2, perhaps explaining its inability to suppress erastin-induced cell death in p53 KO cells (insight into the suppression of ferroptosis by nutlin in parental cells expressing wild-type p53 is provided below)."
sparser
"Many different scaffolds can mimic short α-helices, such as the one formed at the N-terminus of p53 that is bound by HDM2; however, short α-helices can also be mimicked effectively by small organic molecules (such as the nutlins) [ xref ], which suggests that foldamer approaches to this type of target must achieve outstanding performance to have a practical impact."
sparser
"Finally, it is possible that targeting the catalytic activity of MDM2 to reactivate wild type p53 in tumors (which have elevated levels of stress) could open a therapeutic window by avoiding the deleterious on-target side effects of completely disrupting the MDM2-p53 interaction in normal tissue."
reach
"Grossman et al. found that a central domain of MDM2 is able to bind CBP through the N-terminal Taz1 domain using residues distinct from those involved in p53 binding and proposed that a ternary complex may be formed in which the N-terminus of MDM2 binds to p53 TAD1 while the central portion of MDM2 binds to the Taz1 domain of CBP and p300, which is also bound to the p53 DNA binding domain."
sparser
"In conclusion, our in vivo observations were confirmed by in vitro studies showing that BZ/1,4-BQ exposures caused genotoxicity and high expression of miR-222 which obstructed expression of the MDM2-p53 axis that led to failed activation of p53, abnormal DRC and serious biological consequences."
sparser
"The compound from series 20 (R 1 = CH 2 C 6 H 5 , R 2 = CH 2 CH(CH 3 ) 2 , R 3 = CH 3 ), showing the highest ability to dissociate the p53-MDM2 complex (IC 50 = 4.3 nM) and the highest affinity for TSPO (K i = 87 nM), was selected for further biological studies, giving the following results: (i) reactivation of the p53 function and inhibition of the GBM cell growth, triggering subsequent apoptosis; (ii) no efficacy on a GBM cell line expressing mutant p53, supporting the involvement of this protein in the observed effect; (iii) reduction of viability of glioma cancer stem cells (CSCs), which are less sensitive to anticancer agents and responsible for GBM recurrence [ xref ]."
reach
"Our PPI inhibitor profiler is challenged on the experimental screening results of 11 different PPIs among which the p53 and MDM2 interaction screened within our own CDithem platform, that in addition to the validation of our concept led to the identification of 4 novel p53 and MDM2 inhibitors."
reach
"However, currently little is known about how the transmembrane SLC5A7 mediates autophagy attenuation in response to choline treatment, emphasizing the need for further investigation.After activation, SLC5A7 directly binds with cytoplasm p53 and disrupts the interaction between cytoplasm p53 and MDM2 to prevent cytoplasm p53 degradation (23)."
sparser
"More structural information of the γ -AApeptide 19 interaction with MDM2 was collected from the nuclear magnetic resonance (NMR) spectroscopy ( xref – xref ), which coherently indicated that γ -AApeptide 19 interacted with MDM2 at the binding site virtually the same as that of the MDM2-p53 PPI."
sparser
"To demonstrate the feasibility of d -sulfono- γ -AApeptides for the mimicry of helical domain of proteins, we still chose the p53-MDM2 PPI as the model system. xref As shown in xref , like the l -sulfono- γ -AApeptides, the 2a, 4a, and 6a positions in γ -AApeptide 20 were on the same face of the helical scaffold, mimicking the key side chains Phe19, Trp23, and Leu 26 of p53."
reach
"Therefore, the objective of the present study was to evaluate the in vitro effect of treatment with Nutlin-3, a small molecule inhibitor of the MDM2 and p53 interaction, on the expression of the suppressor of cytokine signaling 1 in primary acute myeloid leukemia cells and in myeloid cell lines with differential p53 status."
sparser
"While Schon et al. reported that the same truncation reduced p53 binding to MDM2 by at least 2 orders of magnitude, xref only a modest 16-fold decrease in binding affinity was reported by Lai et al. xref Interestingly, deletion of Glu17 alone from 17–26 p53 was reported to have little impact on p53 binding to MDM2, xref ; xref whereas a 13- and 6-fold decrease in binding affinity for MDM2 and MDMX, respectively, was noted in our work."
sparser
"Exemplary early studies include an exhaustive mutational analysis by Bottger et al. of phage-optimized peptide ligands of MMD2, xref and a comprehensive examination by Schon et al. of the effects of peptide length, non-coded amino acid substitutions and phosphorylation of Ser/Thr residues on p53 binding to MDM2. xref As a result of these pioneering studies, valuable insights have been gained into the molecular determinants of peptide inhibition of the p53-MDM2 interaction."
sparser
"Crystal structure studies of P53 in complex with the MDM proteins have highlighted that three amino acids, Phe19, Trp23, and Leu26, play a key role in the MDM2-P53 interaction, differently from the MDMX-P53 interaction that must be targeted independently from MDM2, opening the doors to the identification of several classes of antitumor agents with different clinical potential [ xref , xref ]."
sparser
"This goal has been obtained through different “molecular strategies” aiming at (i) blocking MDM2 expression, (ii) blocking the physical interaction between MDM2 and P53, (iii) modulating the E3 ubiquitin ligase activity of MDM2, and (iv) targeting the MDM2-P53 (protein–protein) complex."
sparser
"Much of the prior studies have focused on the p53-MDM2 interacting system, and significant progress has been made in the discovery of MDM2-targeted candidate drug molecules. xref ; xref How to design MDMX-specific and, in particular, dual specific antagonists, however, still remains a challenge."
sparser
"The DS3032b compound is an inhibitor of the P53-MDM2 interaction developed by Daiichi Sankyo that has reached the clinical assessment in 2013, and it is now under evaluation in three studies in patients affected by different types of tumors including AML, ALL, CML, MDS (id: NCT02319369 ), advanced solid tumors or lymphomas (id: NCT01877382 ), and relapsed/refractory multiple myeloma patients (id: NCT02579824 )."
sparser
"HDM201 from Novartis is an imidazopyrrolidinone scaffold-based inhibitor of the P53-MDM2 protein–protein interaction with superior characteristics in terms of in vitro activity/selectivity and of in vivo features of oral bioavailability, pharmacokinetic, and pharmacodynamic profiles as assessed in animals [ xref , xref ]."
reach
"For example, the E3 ligase MDM2 has been successfully targeted, with multiple MDM2 inhibitors in clinical trials, including a stapled peptide that targets MDM2 and MDM4, and small molecules that inhibit the protein-protein interaction between MDM2 and p53 (Tisato et al., 2017; Wachter et al., 2017)."
reach
"For instance, the colocalisation of telomeric DNA and promyelocytic leukaemia (PML) protein is a marker of cells that utilise the alternative lengthening of telomeres (ALT) mechanism to maintain telomere length 1, while the E3 ubiquitin ligase Mdm2 binds and negatively regulates the tumour suppressor p53 2."
sparser
"Phosphorylation prevents the binding of p53 with Mdm2, a negative regulator of p53 activation, while acetylation of p53 is central to its DNA-binding activity and upregulation of the downstream mediators, such as PUMA, NOXA, and Bax, responsible for its proapoptotic activity (Tang et al. xref )."
reach
"These results suggest that SARS-CoV-2 spike overexpression can alter p53 binding with MDM2 in cancer cells.However, SARS-CoV-2 spike S2 subunit was not observed to bind with p53 protein in the immunoprecipitation assay (Figure 1A), nor did it have any detectable impact when p53 was activated by treatment with cisplatin, a DNA damaging agent that causes interstrand crosslinks (Figure 1B)."
reach
"The plasmids p-CMV-Neo-Bam-p53wt, pcDNA3.1-SARS2-spike and p-EGFP-MDM2 were co-transfected into p53-knockout U2OS (U2OS-p53KO) cancer cells using lipofectamine.The immunoprecipitation assay showed that MDM2 protein bound with p53 in the cells while cells with SARS-CoV-2 spike overexpression displayed reduced amounts of MDM2 bound with p53 when compared to the pcDNA3.1 transfection control (Figure 1A)."
sparser
"The truncated variant, tetrapeptide 2a , displayed no activity toward Hdm2–p53 complex at concentrations of up to 560 μM. The reconstitution of the original pentapeptide sequence ( 2b ) was indeed required to reproduce the antagonism of p53–Hdm2 interaction, albeit at a relatively high concentration (560 μM)."
sparser
"For instance, the B cell lymphoma-extra large (BCL-X L ) inhibitor ABT-737, which blocks the heterodimerization of the proapoptotic BCL-2-homologous antagonist/killer (BAK) or BCL-2 antagonist of cell death (BAD) to BCL-X L , does not qualify as an interfacial inhibitor; rather, it qualifies as a competitive inhibitor of BAK or BAD to BCL-X L . Similarly, nutlins block the binding of cellular tumour antigen p53 to the oncoprotein HDM2 (also known as MDM2) by binding to the p53-binding pocket of HDM2."
reach
"With respect to the p53 pathway, further studies are needed to unravel how less MDM2 is bound to p53 in the presence of spike and the mechanisms underlying reduced p21(WAF1), TRAIL Death Receptor DR5 as well as MDM2 under conditions where there is less degradation of p53 due to reduced interaction with MDM2.P21(WAF1) and TRAIL Death Receptor DR5 levels often go up in stress and through many pathways but here we see lack of induction."
reach
"Such information would be helpful to patients and physicians as they weigh the risks and benefits of certain medical interventions.In summary, we identified the SARS-CoV-2 spike as a COVID-19 virus factor that interrupts p53 binding to MDM2 in cancer cells and demonstrated the suppressive effect of SARS-CoV-2 spike on p53 signaling in cancer cells."
sparser
"Other proteins, such as Yin Yang1 (YY1) or the focal adhesion kinase (FAK), increase p53 ubiquitination and degradation, mostly by stabilizing the interaction between p53 and Mdm2, an activity that can be counteracted by p14ARF, at least in the case of YY1 (Gronroos et al., 2004; Sui et al., 2004; Lim et al., 2008)."
sparser
"Using fluorescence polarization assays, circular dichroism (CD), NMR spectroscopy, and computational simulations we demonstrate that sulfono-γ-AApeptides adopt helical structures resembling p53 and competitively inhibit the p53-MDM2 interaction by binding to the hydrophobic cleft of MDM2."
sparser
"The predicted pIC50 value of Geissolosimine, was 7.013 M. Moreover, Geissolosimine showed 0.62% structural similarity to ‘SAR405838’ ( i.e., a clinical trial inhibitor for MDM2-p53 interaction inhibition); and a docking score of -10.9 kcal/mol that was higher than the ‘SAR405838’."
sparser
"For example, pre-treatment of cell cultures with Nutlin-3, a highly-selective inhibitor of the p53-mdm2 interaction, has been successfully used as a cytostatic agent to protect normal cells, but not p53-defective cells, from subsequent treatment with mitotic poisons or S-phase specific drugs."
reach
"Molecular interactions between p53, MDM2, and p14ARF fastidiously regulate the balance between the synthesis and turnover of p53, and thus, control the progression of the cell cycle.Functional mutations in TP53 are of considerable significance in neuro-oncology as aberrant p53 expression in glioblastoma multiforme (GBM), a terminal brain tumor, has been associated with worse patient outcomes and decreased chemosensitivity to temozolomide [4, 5]."
sparser
"Many strategies targeting the p53 pathway have been developed, including the restoration of p53 function, the inhibition of p53-MDM2 interaction, and the conversion of mutant p53 into wild-type p53 by gene therapy, the targeting of p53 family proteins, the elimination of mutant p53 , and the development of p53-based vaccines ( xref )."
sparser
"Interaction of wild type p53 with MDM2 are investigated using electrophoretic mobility shift assay on polyacrylamide or agarose gels and DNA foot printing [ xref , xref ], fluorescence anisotropy, chromatin immunoprecipitation [ xref ], ELISA based assays [ xref ], flow analysis [ xref ] and RT-PCR [ xref ]."
sparser
"Moreover, the effect of eIF4A3 knockdown on cell survival (DepMap and DEMETER2) was inversely correlated with the cytotoxicity of RiBi stress–related chemical compounds [e.g., oxaliplatin ( xref ) or the MDM2-p53 inhibitors CGM097 and idasanutlin], strongly implicating eIF4A3 in their mechanism of action ( xref and table S1E)."
sparser
"It is likely that at least some of these MDM2 species are incompetent to bind p53 (or antagonize normal MDM2 transcripts), rendering the MDM2-p53 feedback loop dysfunctional ( xref ) while, at the same time, sensitizing the cells to stressful stimuli that can induce p53, such as ActD L . Targeting eIF4A3 in cancer can thus be beneficial in two ways: (i) through activation of p53 via IRBC and (ii) by sustaining p53 in an active state via attenuation of the MDM2-p53 feedback loop."
sparser
"While the exon-junction complex and its component eIF4A3 are known to secure the transcriptome, preserving the expression of correctly processed full-length mRNAs ( xref ), we define additional critical roles for eIF4A3 in protecting rRNA processing during RiBi and in maintaining a well-functioning MDM2-p53 axis."
sparser
"The general mechanism it appears to do this by is interference of p53-dependent transcription of its target genes by competing for binding to the ACAT sequence on the gene promoters. xref In addition, YY1 has been shown to be essential for optimal interaction of MDM-2 and p53, which is required for MDM-2 ubiquitination of p53. xref The importance of this finding cannot be overstated because an estimated 50% of all tumors have p53-inactivating mutations. xref "
sparser
"Furthermore, dual inhibition of MDM2 and XIAP should result in the activation of p53 in p53 wild-type (p53-wt) tumor cells, similar to MDM2 inhibitors that work by disrupting the binding of MDM2 and p53, but has the added advantage of inducing caspases 3, 7, and 9 that is independent of the p53 status."
reach
"To gain insight into the mechanisms underlying the distinct effects of these two MDM2 inhibitors, we supposed that the MDM2 region targeted may play differential roles in the EMT, as Nutlin-3 targets the N-terminus of MDM2 binding to p53, while HLI-373 targets the C-terminus functioning as an E3 ubiquitin ligase."
sparser
"Nonetheless, ample literature support can be found for the involvement of many of these other assemblies in anti-CDK responses, such as those related to androgen receptor (AR) signaling xref , EGF/fibroblast growth factor (FGF) signaling xref , DNA damage response xref and the MDM2–p53 pathway xref ."
sparser
"This review uses the p53-MDM2 to show how different techniques can be employed, illustrating how a combination of in vitro and in vivo techniques is highly recommended to study the spatio-temporal location and dynamics of interactions, and to address their regulation mechanisms and functions."
sparser
"Using synthetic and p53-derived peptides from phage display libraries, EIA/ELISA was applied to confirm the role of residues F19, W23, and L26 as critical contact points on p53 when interacting with MDM2 [ xref ] ( xref ), as previously suggested by the crystal structure of the p53-MDM2 interface [ xref ]."
sparser
"Nonetheless, the low background in the BRET signal and its simple implementation attest for the convenience to use it for high-throughput screening of drugs in living cells [ xref ] and the p53-MDM2 interaction has served as a model system to explore such a capacity using the well-known MDM2-inhibitor Nutlin-3a [ xref ] ( xref )."
sparser
"Using F2H, several cell-penetrating compounds were shown to potently inhibit p53-MDM2 interaction without affecting binding of p53 to MDMX [ xref ], which is in agreement with the effect of previously-reported antagonists that are several magnitudes less potent in disrupting the p53-MDMX interaction when compared to the p53-MDM2 counterpart [ xref ]."
sparser
"The p53-MDM2 regulation mechanism provides with a fine model, which, over the past decades, has triggered the development and refinement of several techniques described here, which are continually leading to improved approaches and technologies, that favour the sophistication of the available molecular toolsets."
sparser
"In the current study, we show increased expression and phosphorylation of p53, and decreased viability in a dose-dependent manner after treatment with nutlin-3 in wild-type p53 cell lines ( xref ), indicating that inhibition of MDM2–p53 interaction has an important biological function in mesothelioma."
reach
"Indeed, a recent study reported that maintaining theexpression of wt p53 in DC by inhibiting the p53 and MDM2 interaction with Nutlin-3, actually enhanced T cell proliferation in vitro even though DC activation markers were not affected.30 While we could not detect any p53 dependent effect onantigen specific T cell proliferation in our experiments, possibly attributable to our in vivo model, we have shown that the generation of antigen specific cytotoxic effector cells in vivo is strongly influenced by p53 expression and that p53 clearly affects the efficacy of vaccination with BMAPC."
reach
"This explanation of how combined SNPs and haplotypes can regulate MDM-2 binding to p53, which in turn can regulate p53 levels and activities, which in turn can regulate the selection pressure for TP53 spontaneous mutations in a cell (mutation incidence), and even the age of onset of a tumor initiated by a TP53 mutation, is a reasonable way to understand the phenotypes discussed in this manuscript."
sparser
"Upon cellular stress, several kinases phosphorylate p53 at the N‐terminal serine and threonine residues that inhibit p53–MDM2 interaction and promote p53 stabilization, which translocate to both the nucleus and the mitochondria. xref In the nucleus, p53 binds to response elements within the promoter and induces the expression of proapoptotic members of the B‐cell lymphoma‐2 (BCL‐2) protein family, including p53 upregulated modulator of apoptosis (PUMA), xref nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activator (NOXA), xref and BCL‐2‐associated X‐protein (BAX). xref In the mitochondria, p53 activates the proapoptotic proteins BAX and BCL‐2 antagonist/killer (BAK) xref but inactivates the antiapoptotic proteins BCL extralarge (BCL‐xL) xref and BCL‐2, xref which in turn inactivates BAX."
reach
"It may be noteworthy that five of the ribosomal proteins that regulate MDM2 and p53 interactions had significantly differential expression in W98S/D neural crest progenitors including RPL5 (1.244-fold), RPL11 (0.886-fold), RPL12 (0.748-fold), RPL23 (0.870-fold) and RPS15 (1.169-fold; XREF_TABLE)."
sparser
"Inhibitors
such as RG7112 (analogous to nutlin) cause MDM2 inactivation leading
to increased cellular apoptosis and cell cycle arrest showing a reduction
in tumor growth in xenografts. xref Nutlin-3a
is known to inhibit the MDM2-p53 interactions and enhance p53-mediated
apoptosis in osteosarcoma. xref Other inhibitors
of MDM2 such as CGM097, MK8242, MI77301, and RG7388 are known to be
used in various cancers although only a few are known to play an important
role in the therapeutics of GBM. xref − xref Studies have also shown that
inhibiting MDM2 can also be a therapeutic option in treating GBMs
possessing wild-type p53. xref , xref These studies prove
that MDM2 can be an effective target in tumorgenicity and breaking
the p53-MDM2 interactions can be significant in GBM treatment."
sparser
"This interaction prevents p53 from binding to the transcriptional activation domains of its target genes; (2) The central region of Mdm2 (the acidic domain) interacts with the sequence-specific DNA binding domain (DBD) of p53, a key step for p53 ubiquitination [ xref , xref ]; (3) The N-terminal domain of Mdm2 also interacts with the C-terminal domain of p53, a region necessary for post-translational modifications such as phosphorylation and ubiquitination."
sparser
"Mouse double minute 2 homolog (MDM2) is an E3 ubiquitin ligase that binds to tumor suppressor p53, causing the subsequent degradation by ubiquitin. xref – xref Compared to the other E3 ligases (von Hippel–Lindau (VHL), or cereblon (CRBN)) used in PROTACs, MDM2 is unique in that its endogenous substrate, the tumor suppressor p53, plays a major role in tumor suppression. xref In response to the cellular stress, DNA damage, and hypoxia, p53 is upregulated and induces pathways that cause cell cycle arrest, DNA repair, cellular senescence, differentiation, and apoptosis. xref – xref Overexpression of MDM2 can reduce the expression of p53 through the negative feedback pathway. xref – xref Inhibition of MDM2 protein blocks MDM2-p53 interaction, up-regulates the expression of p53 and thus exerts antitumor activity. xref – xref Several small-molecule MDM2-p53 inhibitors have entered clinical trials. xref – xref "
sparser
"Alkaloids represent an important class of natural compounds
and are shown to induce cell death in GBM as they are potent antioxidants. xref Alkaloids such as melatonin (monoamine alkaloid)
are able to inhibit MDM2 in the MCF7 breast cancer cell line. xref Melatonin is also known to inhibit phosphorylation
of MDM2, enhancing acetylation of p53 thereby leading to p53-MDM2
disruption and gain of functions of p53. xref Another study found that papaverine (non-narcotic opium alkaloid)
was able to induce suppression in GBM activity. xref Evodiamine is a natural alkaloid derived from the fruit
of Evodia rutaecarpa (medicinal plant)
mostly used by the Chinese in medicine. xref This alkaloid is known to exhibit the property of anti-inflammation
and is known to be reported in reducing the proliferation of cancerous
cells by the process of apoptosis and cell cycle arrest. xref Evodiamine was found to induce calcium/JNK-mediated
autophagy and mitochondrial-mediated apoptosis in GBM. xref , xref However, the role of evodiamine in targeting MDM2 as a ubiquitin
E3 ligase remains unclear."
sparser
"However, the role of sanguinarine
in targeting MDM2 is not understood
and how these alkaloids can be the potential inhibitors of ubiquitin
E3 ligase is also unknown. xref Studies have
shown that alkaloids can induce self-ubiquitination and degradation
in MDM2 by targeting MDM2-DAXX-HAUSP interactions. xref Alkaloids such as berberine, matrine, and melatonin are
reported to be effective in reducing the expression of MDM2 or decreasing
the stability in acute lymphoblastic leukemia, liver carcinoma, and
breast cancer. xref , xref Other studies in which alkaloids
can be seen in altering the MDM2-p53 signaling are indole-3-carbinol xref and fluspirilene xref targeting breast and colon cancer."
sparser
"The activation domain of p53 adopts an α-helical
conformation when bound to Mdm2, xref and
several classes of stabilized helices and helix mimetics have been
shown to target this interaction. xref , xref , xref , xref − xref In addition, several potent small molecule inhibitors of this interaction
are known and are being evaluated for their in vivo efficacy in advanced preclinical models. xref − xref Lastly, a wealth of structural
data on the p53–Mdm2 interaction makes it well suited for
development of computational strategies xref for ligand optimization. xref , xref − xref "
reach
"Based on our observation that cells could overexpress ubiquitin ligase defective MDM2, we speculate that therapeutic approaches that suppress the ubiquitin ligase activity of MDM2 may not be as effective in restoring p53 function as preventing formation of the MDM2 and p53 complex."
reach
"Since the expression of MDM2 was found to be upregulated in one-third of high-grade ChS and correlated with increasing histopathological grade [XREF_BIBR], the inhibition of interactions between p53 and MDM2 by small-molecule agents (e.g., RG7112) restoring the function of p53 may be a rational therapeutic intervention in ChS [XREF_BIBR]."
| PMC
sparser
"Furthermore, the VDWIs of the inhibitors with MDM2 play key roles in the binding of the two types of inhibitors, which implies that the hydrophobic groups of the peptide and non-peptide inhibitors, such as alkyls and aromatic rings, are significant molecular structures to be considered in future drug design in relation to p53-MDM2 interactions."
sparser
"USP7, also known as herpes virus associated protease (HAUSP), regulates the deubiquitination of histone H2B monoubiquitinion (H2Bub1) [ xref ] and the stability of multiple proteins including p53-MDM2 [ xref , xref ], β-catenin [ xref ] PTEN [ xref ], and FOXP3/4 [ xref ], and is involved in diverse cellular processes including DNA transcription, DNA damage response (DDR), epigenetic control of gene expression, immune response, and viral infection [ xref ]."
sparser
"Nutlins were the first potent and selective inhibitors of the MDM2-p53 interaction (Vassilev et al., xref ), in particular Nutlin-3 has been extensively evaluated in vitro and in vivo in several types of human cancers and the cis -imidazoline RG7112 is currently in phase I clinical trials xref (NCT00559533 and NCT00623870)."
sparser
"To ensure comparable activity and DNA damage responses of SpCas9 and enAsCas12a, the cellular proliferation of RPE1 cells was monitored upon transduction with sgRNAs targeting TP53 in the absence and presence of Nutlin-3 xref , a small molecule that blocks the TP53-MDM2 interaction, causing a TP53 -dependent cell cycle arrest."
sparser
"The p53 gene is intact (i.e., not deleted, mutated, or methylated) in most RCC. xref P53 has been implicated as a master regulator of a variety of cellular processes, including proliferation, senescence, differentiation, apoptosis, ferroptosis, DNA repair, metabolism, angiogenesis, and autophagy. xref We found a decrease in p53 expression under sorafenib, consistent with previous reports. xref Designing small molecules to block the MDM2-p53 interaction and reactivate p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. xref In this study, we found that RITA, an activator of p53, can inhibit the occurrence of therapy resistance when combined with sorafenib."
sparser
"After the onset of ischemia, p53 is rapidly activated by phosphorylation in its N‐terminal region. xref In this context, the activation of protein kinases triggered by DNA damage or excitotoxicity after ischemia xref promotes p53 phosphorylation at key residues and then disturbs the p53–MDM2 interaction, which results in p53 stabilization and determines its nuclear and mitochondrial trafficking and proapoptotic activity. xref In this situation, calcium overload in response to excitotoxicity activates death‐associated protein kinase 1 that phosphorylates p53 at serine 20, leading to neuronal death. xref Cyclin‐dependent kinase 5 (Cdk5) is also activated in response to glutamate‐mediated neurotoxicity in postmitotic neurons xref , xref and phosphorylates different substates, including p53 at serine 15, linking excitotoxicity and neuronal death. xref Moreover, Cdk5 inhibition attenuates p53‐dependent apoptosis after cerebral ischemia. xref Finally, ischemia‐induced DNA damage and oxidative stress also induces p53 phosphorylation at serine 15 through a mechanism dependent on protein kinase ataxia‐telangiectasia mutated activation. xref "
sparser
"In this sense, numerous tumor suppressor approaches are related to p53-MDM2/MDMX, namely preventing the formation of p53-MDM2 complexes, preventing the p53 protein ubiquitination degradation and modifying p53 transcriptional active region to stabilize the p53 protein [ xref , xref , xref , xref ]."
sparser
"Overall, they include the use of small molecule or peptide stabilizers of misfolded p53, zinc administration, gene therapy, metallochaperones, alkylating and DNA intercalators, [ xref ] blockage of p53-MDM2 interaction, impaired reactive oxygen species (ROS) detoxification and other p53 regulators [ xref , xref , xref , xref ]."
sparser
"Indeed, the synthesis and initial SAR of rigid cores capable of holding two aromatic rings in proximity had led Sun and co-workers closely before in the same year to the identification of a piperidinone derivative as a novel inhibitor of the MDM2-p53 protein–protein interaction [ xref ]."
sparser
"In 2013, Sheng, Zhang and co-workers reported the synthesis of a set of pyrrolo[3,4- c ]pyrazole derivatives 197 that were excellent simultaneous inhibitors of p53-MDM2 and NF-κB (five DNA-binding proteins that are often hyperactive in cancer and inflammatory processes) [ xref ]."
sparser
"This compound induces both DNA-protein and DNA-DNA cross-links with no detectable DNA single-strand breaks, and has also been shown to inhibit the p53-MDM2 interaction as well as target p53 mutants R175H, R248W, R273H, and R280K, restoring transcriptional activity and inducing apoptosis [ xref , xref ]."
sparser
"In the last decades, a lot of groundbreaking work was conducted regarding the development of small molecules for p53 reactivation, and two main pathways have been especially highlighted: (1) Molecules that can react covalently with the thiol groups in the cysteine residues of mutant p53, which leads to conformational changes that can reactivate the protein and (2) molecules that are able to disrupt the MDM2-p53 protein complex, releasing the WTp53 protein to resume its function."
sparser
"Because our previous work has shown that seizure itself can induce ER stress and that the induced Mdm2-p53 signaling following a seizure functions to homeostatically reduce neuronal excitability ( xref ), our current data indicate a possibility that Fmr1 KO may have difficulty in homeostatically reducing excitability following a seizure attack."
sparser
"In cancers with wild-type TP53, reactivating its wild-type function by small molecule antagonists, which disrupt the interaction of p53 and MDM2, has been an attractive strategy. xref , xref Radiation therapy (RT) is an integral component of treating liposarcoma, activates the p53 pathway, and executes its effect by cell cycle arrest, apoptosis, and senescence."
sparser
"In synthesis, in the context of liposarcoma, it can be emphasized that disruption of MDM2-p53 interaction and reactivation of p53 by coapplication of MDM2 inhibitor and RT led to radiosensitization (SER greater than 1) as a long-term fate via attenuated clonal ability and senescence in the relatively abundant polyploid population ( xref C), which emerged either by cytokinesis failure or cell fusion."
sparser
"The interaction
between p53 and MDM2 is essentially hydrophobic. xref − xref This principle
has been used to design inhibitors that block p53 and MDM2 binding, xref and some of them are entering clinical trials. xref Our ongoing MD simulations of this complex also
show dewetting phenomena for this system."
sparser
"Taken together, these data demonstrated that: 1) the MDM2-p53 complex degradation mediated by WB214 is through the ubiquitin-proteasome machinery; 2) p53 is a bystander during the degradation of MDM2 because of its direct association with MDM2; and 3) the WB214- CRBN complex does not bind to MDM2 in the p53 binding region, which is where MDM2 ligand 1 or WB138 binds to."
sparser
"Our data also indicate a role for ribosome biogenesis in the transition from virus-induced arrest to senescence, likely through a p53-MDM2 axis, xref which regulates EBV transformation. xref Chromatin closure in EBV-induced arrest was enriched at loci linked to B cell activation, signaling, and proliferation."
sparser
"In this review, we describe the influence of MDM2 on genomic instability, the role of MDM2 on releasing p53 and binding DNA repair proteins to inhibit repair, and the regulation network of MDM2 including its transcriptional modifications, protein stability, and localization following DNA damage in genome integrity maintenance and in MDM2-p53 axis control."
sparser
"On the one hand, the N‐terminal domain of MDM2 interacts with the transactivation domain of p53 and inhibits its transcriptional activity. xref On the other hand, the E3 activity of MDM2 is dependent on its C‐terminal RING finger domain that polyubiquitinates p53 for proteasomal degradation."
sparser
"Previous research has demonstrated an interaction between MDM2 and TP53 at the molecular level xref , and the combined effects of MDM2 SNP 309 and TP53 Arg72Pro have been examined in lung cancer, Li–Fraumeni syndrome and non-polyposis colorectal cancer, with conflicting results xref , xref , xref ."
sparser
"Stress‐induced p53 phosphorylation decreases p53–MDM2 interaction, leading to protein accumulation and tetramerization, which conceals OD NES and then retains p53 in the nucleus. xref In addition, the TAD NES contains serine residues phosphorylated after stress, particularly serine 15, which results in NES inhibition and collaborates with p53 export blockage. xref Moreover, phosphorylation also results in p300‐induced acetylation of lysine residues in CTD to promote p53 stabilization xref (Figure xref )."
sparser
"The increased MDM2 protein levels observed after ischemic preconditioning (sublethal ischemia) lead to p53 cytosolic destabilization and prevent p53‐mediated apoptosis after subsequent ischemia. xref On the contrary, treatment with the specific inhibitor Nutlin‐3a that disrupts p53‐MDM2 binding negatively affects neuronal survival after ischemia. xref Furthermore, the MDM2–p53 interaction has been found to be neuroprotective in stroke patients and a reliable predictor of functional outcome after stroke."
reach
"Navtemadlin (previously KRT232 and AMG232) is an orally bioavailable, selective small molecule inhibitor of MDM2 that blocks the protein-protein interaction between MDM2 and p53 [5, 8], with an in vitro half-maximal inhibitory concentration (IC ) of 1.0 nM in a homogeneous time resolved fluorescence based assay [8]."
reach
"Given that the chemical shifts of 15 N-Val14 and 15 N-Ala21 of (1-24) MDM2 in its free form (XREF_FIG) were nearly identical to the values obtained for (1-109) MDM2 in complex with (15-29) p53, it is obvious that binding of (15-29) p53 to (1-109) MDM2 displaces the partially structured lid peptide, leaving it fully disordered and in no direct contact with the peptide protein complex."
sparser
"Several MDM2 inhibitors have been developed, the best described being nutlins, a family of small molecules blocking the p53-MDM2 interactions leading to stabilization of p53. xref These drugs have been evaluated in patients with solid cancers and hematological malignancies with promising results."
reach
"The large increase in sites after Nutlin compared with DXR treatment was unexpected and suggests that Nutlin treatment leads to changes in chromatin architecture or nucleosome occupancy that are not anticipated for a drug selected for its specific effect on the interaction between p53 and MDM2."
reach
"20 Thus, further structural simplification led to the identification of spiro-pyrrolidinyl MI-888 (5) as a potent nonpeptide inhibitor of p53 and MDM2 interaction (K i = 0.44 nM), which was reported to achieve rapid, complete, and long lasting tumor regression in two types of xenograft models of human cancer, with oral administration."
sparser
"At early time after Pten ablation, Mdm2 (mouse double-minute 2) is phosphorylated (P-Mdm2), most probably by P-Akt, and p53 is downregulated, until DNA damage responseinduced Casein Kinase I (CkI) levels are sufficient to promote Mdm2 degradation and/ or impair the interaction between Mdm2 and p53."
sparser
"Phase 1 clinical study has investigated AMG 232, a selective MDM2 inhibitor that restores p53 tumour suppression by blocking the MDM2–p53 interaction with picomolar affinity [ xref ] appears to be safe and could provide a strategy to target CDKN2A deleted MPMs, which harbour wild-type p53."