IndraLab

Statements

TP53 binds MDM2 and MDM4. 305 / 305
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"Our ongoing interest in the rational design of small molecule antagonists of the p53 Mdm2 and Mdm4 interactions has prompted us to design scaffolds with novel tryptophan mimicking features. xref While Wang et al. introduced the oxindole anchor, we introduced indole and others are using p-substituted phenyl groups, we wanted to explore here the benzimidazolidinone moiety as a tryptophan mimicking moiety. xref For reasons of resources we restricted our search of suitable benzimidazolidinone scaffolds to multicomponent reactions as opposed to sequential multi step syntheses."
22789708
sparser
"The association of p53 with MDM2 and MDM4 is disrupted with phosphorylation by various enzymes such as DNA-PK, ABL, ATR, ATM and CHK -all activated by genotoxic stressors [ xref ]."
25152696
sparser
"The ability of DIMP53‐1 to block the p53 interaction with MDM2 and MDMX was demonstrated by Co‐IP, in HCT116p53 +/+ cells."
28296148
sparser
"One goal of this study was to understand how non-enzymatic interaction of MdmX with p53 and Mdm2 can regulate p53 during the response to DNA damage."
20174603
sparser
"In contrast, binding of MDM2 and MDM4 to p53-S20D mutant was markedly lower than to wild-type p53."
28031409
sparser
"By mimicking this region, ALRN-6924 can bind the 2 most important endogenous inhibitors of p53, MDM2 and MDMX."
31289443
sparser
"Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX."
19255450
sparser
"MdmX and Mdm2 can dynamically bind to p53 at the transactivation domain and prevent p53 target genes from being transcribed xref ( xref )."
19543236
sparser
"Studies from these mouse models have suggested that blocking the interaction of Mdm2 and/or Mdm4 with p53 could be a potential therapeutic strategy for cancer patients with wild-type p53 alleles."
23327795
sparser
"Overexpressed MDM2 and MDMX bind to p53 directly, resulting in dysfunction of p53."
31689961
sparser
"One of the earliest targeted therapies envisioned for use in retinoblastoma, based on preclinical information generated in transgenic mice, was Nutlin-3. xref Nutlin-3 blocks the interaction of MDM2 and MDM4 with p53, resulting in stabilization of p53 and stimulation of apoptotic cell death."
27189421
sparser
"In particular, NAPA 9, which has a bromine at position Y, inhibited HDM2 and HDMX binding with p53 two to four times better than a derivative with a hydrogen at the same position (NAPA 5)."
19880322
sparser
"Mdm2 and MdmX can directly interact with p53 and inhibit its transcription activity ( xref ; xref ; xref )."
31024344
sparser
"Together, these results demonstrate that ALRN-6924 is cell-permeable, disrupts both p53-MDMX and p53-MDM2 interactions, and displays on-target p53 pathway activity in AML cells."
29643228
sparser
"In summary, using the p53 peptide imitating strategy, several promising mimetic peptides or small molecules that could inhibit the interaction of MDM2 and/or MDMX with p53 have been discovered."
25201201
sparser
"In addition, the interaction between p53 and Mdm2 or MdmX suppresses the transcriptional activities of p53 [3] ."
20061153
sparser
"Clearly, interrupting the MDM2-MDMX-p53 interaction is indispensible for p53 activation, and yet, remarkably, one of p53's direct transcriptional targets is MDM2 itself, indicating that regulation of p53 by MDM2 occurs through a negative-feedback loop ( xref )."
28351719
sparser
"Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay."
25814188
sparser
"MDM2 (an ubiquitin ligase mouse double minute-2 homologue; called HDM2 in humans) and MDM4, which bind to the amino terminus of p53, are responsible for inhibiting p53 and promoting its degradation ( xref )."
19707334
sparser
"Therefore, the development of inhibitors of both HDM2 and HDMX binding to p53 is becoming an important new target for chemists to tackle. xref Recently, the work of Schepartz and co-workers has elegantly demonstrated that helical α-peptides can be appropriately modified to bind with good affinity to both HDM2 and HDMX. xref Here, we report an alternative scaffold based on the α-sheet tri-urea template developed by Nowick and co-workers. xref Among the inhibitors of p53-HDM2, Robinson and co-workers showed that peptide-based structures other than a helix can be developed into inhibitors. xref In this work, cyclic peptides in α-sheet conformations were developed into very potent inhibitors of HDM2-p53 association. xref – xref Based on these precedents, we have developed a scaffold we have termed N-acylpolyamines (NAPAs, xref ) and we have optimized the sidechains projecting from the scaffold to inhibit both HDM2 and HDMX binding to a p53 peptide with IC 50 values around 2 μ M. As illustrated in xref , our general strategy was to project hydrophobic sidechains from the urea (R i ) to bind into the proteins’ hydrophobic binding clefts while sidechains attached to the carbon backbone (R o ) would be hydrophilic and exposed to the solvent."
19880322
reach
"Although our data indicate that FAM193A controls the dynamics of the MDM4/MDM2/p53 complex primarily through modulation of levels of the individual components of this complex, it is possible that FAM193A binding to the RING domain of MDM4 may interfere with the activity of the MDM2-MDM4 heterodimer, leading to higher p53 protein expression and activity."
36897777
sparser
"Small molecule antagonists that inhibit the interactions between p53 and MDM2 or MDMX are likely to cause “off-target” toxicity due to poor binding affinity and specificity."
36185610
sparser
"However, to our surprise, INZ or its close analogue INZ1 that induced p53 did not apparently affect the interaction between either MDMX and p53, or MDM2 and MDMX, or MDM2 and p53 in our in vitro fluorescence polarization and cell-based co-immunoprecipitation assays (data not shown)."
22331558
sparser
"More recently, the strategies to target p53 involve the dual inhibition of the p53-MDM2 and p53-MDMX interactions to effectively activate wild-type p53."
27187415
sparser
"Small chemical compounds have been developed to block the MDM2-p53 or MDMX-p53 interaction ( xref )."
33568521
sparser
"Inhibitors that disrupt the interaction between p53 and MDM2 and/or the homologue MDMX (also known as MDM4) were developed xref , including the cis -imidazoline analogues (otherwise known as the nutlins) such as Nutlin-3 and RG7112, which are currently being assessed in clinical trials for haematological malignancies xref ."
29242641
sparser
"Low-Molecular-Weight Inhibitors of Mdm2–p53 and Mdmx–p53 Interactions."
21341346
sparser
"In cancers, where expression of wild- type TP53 is maintained, it is often associated with the expression or amplification of a p53 negative regulator such as Mdm2 or Mdmx."
25427447
sparser
"Our results indicate that it is possible to develop non-peptidic synthetic molecules with equal inhibitory activity against both HDM2 and HDMX binding to p53."
19880322
sparser
"RO-5963 has been identified as a dual inhibitor of MDM2-p53 and MDMX-p53 interactions."
24180275
sparser
"Evaluate if SAH peptides disrupt p53-Mdm2 and p53-Mdm4 interactions in living cells."
25464845
sparser
"These authors postulated that their peptides might insert themselves into a hydrophobic cleft involved in binding of MDM2 and MDMX to p53 disrupting this binding."
21266016
sparser
"The inhibitors of protein-protein interactions (PPIs) of MDM2-p53 and MDMX-p53 represent potential anticancer agents."
23726030
sparser
"In tumors with wild type p53, activation of p53 to induce apoptosis can be achieved by blocking Mdm2 or Mdm4 binding to p53 (Martins et al., xref ; Shchors et al., xref ; Ventura et al., xref ; Wang et al., xref ; Xue et al., xref )."
25073422
sparser
"In addition to our observations, several studies have shown that the side chain of L22 contributes to the binding of p53 to both Mdm2 and MdmX."
26812210
sparser
"Several small molecule and peptide-based compounds have been reported to interfere with p53-Mdm2 and p53-Mdm4 interactions in biophysical assays and to activate p53 in living cells ( xref ; xref )."
25464845
sparser
"Both apamin and stingin adopt nearly identical structures where an N-terminal loop and a C-terminal α-helix are stabilized by two disulfide bridges (Cys1–Cys11 and Cys3–Cys15). xref , xref By grafting the four underlined hydrophobic residues (Phe9, Tyr12, Trp13, and Leu16) to apamin, we succeeded in converting the neurotoxin into a potent inhibitor of the interaction of the p53 tumor suppressor with its negative regulators MDM2 and MDMX. xref "
23660015
sparser
"PMI competes with p53 for MDM2 and MDMX binding at an affinity roughly two orders of magnitude higher than that of 17–28 p53 (ET F SDL W KL L PE) of the same length; both peptides adopt nearly identical α-helical conformations in the complexes, where the three highlighted hydrophobic residues Phe, Trp and Leu dominate PMI or 17–28 p53 binding to MDM2 and MDMX."
20226197
sparser
"Cisplatin resistant cells, however, can demonstrate increased binding of both MDM2 and MDM4 to p53, but in absence of cellular overexpression."
32063580
sparser
"As Hsp90 binds to MDM2 and p53, xref , xref and MDM2 binds to p53 and MDMX, xref we determined whether 17AAG could affect these interactions."
21562588
sparser
"The USP7 NTD is a TRAF domain that is known to bind p53, Mdm2 and MdmX in addition to the viral EBNA1 protein xref , xref , xref , xref ."
21305000
sparser
"The aforementioned p53-derived stapled peptide, ALRN-6924, represents another approach to disrupt protein-protein interactions between p53 and both MDM2 and MDMX (Bernal et al., 2010; Brown et al., 2013) ."
35155432
reach
"The stoppin peptide is a potential antitumor drug because it is an inhibitor of the p53, MDM2, and MDMX complex."
33817095
sparser
"However, further study will be required to determine whether ECCA also involves the regulation of interactions of p53 and MDM2 or MDMX, which usually suppress p53 activation in melanoma cells xref ."
34103468
sparser
"This model is supported by data demonstrating that loss of the p53 interaction with either Mdm2 or MdmX, is essential for the activation of cell cycle-specific target genes ( xref )."
19450511
sparser
"Yet, further studies showed that exo-PpIX is a dual inhibitor of the MDM2-p53 and MDMX-p53 interactions, as depicted in a yeast-based reporter assay, fluorescence two-hybrid assay and immunoprecipitation [ xref ]."
32971841
sparser
"MdmX and Mdm2 both bind to the promoters of p53-responsive genes and form a 3 protein complex with p53 by interacting with the transactivation domain [ xref – xref ]."
21624367
sparser
"Heterodimers of MDM2 and MDM4 bind to p53 through their N-terminus and activate the E3 ligase activity of MDM2 to induce proteasomal degradation of the p53 protein [ xref – xref ]."
29662640
sparser
"Our study demonstrated that MDM2 rs2279744 interacts with the TP53 rs1042522 variant and MDM4 rs4245739 with the MDM2 rs3730485 variant."
32492903
sparser
"Recently, a dual Mdm2/Mdm4 antagonist RO-5963 ( xref ) was identified that blocks p53 interaction with both Mdm2 and Mdm4 by inducing formation of homo- or hetero-dimers between Mdm proteins through their p53-binding domains ( xref )."
23262034
sparser
"Through the use of chemical hydrocarbon stapling, Bernal et al. xref developed a stapled peptide (SAH-p53-8) that is capable of blocking the interactions of both MDM2 and MDM4 with p53."
36216888
sparser
"Proof of this concept was recently demonstrated where a 12-mer peptide was identified that inhibited both the MDM2:p53 and MDMX:p53 interactions [ xref ]."
24756955
sparser
"Although reduced p53 stability in 2780CP/Cl-16 cells was associated with moderate cellular overexpression of MDM2 or MDM4 (<1.5-fold), their binding to p53 was substantially enhanced (5- to 8-fold)."
26876197
sparser
"Unpublished observations in our laboratory also suggest that MDM2−p53 or MDMX−p53 interaction may not be sufficient for p53 suppression in the adult mouse."
28096294
sparser
"Recent availability of the crystal structure of the N-terminal domain of MDMX bound to a 15-residue p53 peptide showed that although basic features of the MDM2-p53 and MDMX-p53 interactions are similar, there are some differences between the binding pockets in MDM2 and MDMX ( xref )."
18834305
sparser
"As the principal negative regulators of p53, MDMX and MDM2 form a MDM heterocomplex that works together in p53 control."
25974965
sparser
"Previous in vitro studies suggested that the primary mechanism of MDM2- and MDMX-dependent p53 inhibition was mediated through direct MDM2 and MDMX binding to the p53 transactivation domain, causing disruption of p53 activity."
28096294
sparser
"We previously showed that p53-Mdm2 or p53-Mdmx interactions subsequent to DNA damage are readily detectable as long as proteasome inhibitors are present ( xref ; xref ), implying that p53 post-translational modifications alone are insufficient to prevent interactions with Mdm2/Mdmx."
19573810
sparser
"Nutlin-3a is a small molecule that blocks MDM2-mediated p53 degradation, and thereby leads to cell death in cancer cells and tumor xenografts. xref It synergizes with conventional chemotherapeutic agents and is currently undergoing phase I and II clinical trials as combination therapy. xref , xref Inhibiting the interaction of p53 with MDM2 or MDMX using small molecules represents an attractive strategy for treating human cancers that bear wild-type p53 but overexpress MDM2 or MDM4; xref , xref , xref however, this concept has rarely been tested in HNC. xref , xref A heat shock protein 90 (Hsp90) inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17AAG), was reported to interfere with the repressive p53–MDMX complex and increase p53 transcriptional activity by inducing MDMX degradation. xref This non-genotoxic small molecule selectively decreases the viability of solid cancer cells and increases the apoptotic activity of Nutlin-3a."
24336076
sparser
"The discovery of novel p53-MDM2/X inhibitors was one of the highlights in anti-tumor agents. xref Since the disclosure of Nutlin-3, xref many scaffolds have been prepared and evaluated, including indo-imidazole, imidazoline, benzodiazepinedione and spirooxindole scaffolds. xref Thus, antagonizing the p53-MDM2 or/and MDMX interaction is a promising anticancer strategy and several compounds are presently undergoing early clinical evaluations. xref – xref However, the discovery of new p53/MDM2/MDMX scaffolds is still of high interest due to low single agent activity currently seen in clinical trials and insufficient PKPD properties."
26584879
sparser
"In the light of these observations, the radiosensitising properties of the nutlin-3 and topotecan combination may be safely enhanced further by dual inhibition of p53-MDM2 and p53-MDMX interactions or by inhibition of Wip1."
30018737
sparser
"ALRN-6924 is the newest stapled peptide that binds equally to MDM2 and MDMX and disrupts both the MDM2–p53 and MDMX–p53 interactions."
27327543
sparser
"P53 primarily interacts with both Mdm2 and Mdm4 via its intrinsically disordered N-terminal transactivation domain (TAD), which forms an α-helix when bound to the N-terminal p53 binding domain of either protein xref , xref ."
31784573
sparser
"To further test the role of MDM2 and MDMX in regulating p53 level and activity in TGCT cells, an adenovirus expressing thioredoxin fused to an optimized inhibitory peptide against MDM2 and MDMX (Ad-DI) was also used to disrupt MDM2-p53 and MDMX-p53 binding. xref Because of extremely poor efficiency of gene delivery by adenovirus in TGCT cells, the experiment using 833KE and 2102EP were uninformative (data not shown)."
20372076
sparser
"Grafting four residues of p53 critical for MDM2/MDMX binding to the N-terminal alpha-helix of BmBKTx1, a scorpion toxin isolated from the venom of the Asian scorpion Buthus martensi Karsch, converts the miniature protein into an effective inhibitor of p53 interactions with MDM2 and MDMX."
18798622
sparser
"In contrast, the SAHp53-8, sMTide-02, and ATSP-7041 were potent p53-Mdm2 and p53-Mdm4 interaction disruptors in the lysate BiLC assays ( xref ); negative control peptides with mutations in amino acids (Phe, Trp and Leu) known to mediate p53 interactions with Mdm2 and Mdm4 were inactive ( xref )."
25464845
sparser
"The strategy consisting of dual inhibition of the p53-MDM2 and p53-MDMX interactions has shown promise in pre-clinical testing [ xref ]."
30018737
sparser
"MDM2 knockdown was associated with mild accumulation of MDM4 and p53, as well as the product of the downstream gene p21 ."
25621298
sparser
"In conclusion, by grafting four hydrophobic residues, critical for MDM2/MDMX binding, to the C-terminal α-helix of apamin, we successfully converted the bee-venom neurotoxin into a series of potent inhibitors of p53 interactions with MDM2 and MDMX."
19827079
sparser
"Expression of a scaffold protein (thioredoxin) displaying this peptide sequence by adenovirus disrupts both MDM2 and MDMX interaction with p53, resulting in efficient p53 activation, cell cycle arrest, and apoptosis of tumor cells overexpressing MDM2 and MDMX."
17875722
sparser
"P53 activity is mainly inhibited by Mdm2 and MdmX (Mdm4). xref We therefore wondered whether binding of p53 to Mdm2 and MdmX is altered in mESCs and differentiated cells."
25719246
sparser
"The binding of MDM2 and MDM4 to p53 provides a stringent test of a method’s ability to distinguish between subtly different homologous protein-protein[ xref – xref ] interactions."
28837642
sparser
"The interaction between Mdm2 and/or Mdm4 and p53 has become an important model system for the design and development of drug-like molecules that disrupt intracellular protein–protein interactions, leading to substantial development in drug discovery."
28077607
sparser
"Three different classes of small-molecule MDM2 antagonists are currently under clinical investigation ( xref ) and, in addition, p53-stapled peptides have emerged as a promising modality for the p53-Mdm2 and p53-Mdmx interactions ( xref ; xref )."
24207125
sparser
"Unlike the small molecule inhibitors of MDM2 in clinical development, ALRN-6924 (Aileron Therapeutics) is a stapled peptide designed to disrupt p53 interaction with both MDM2 and MDM4 and currently in phase I/II clinical trials in solid and haematological malignancies (identifier NCT02264613 and NCT02909972)."
28096293
reach
"XREF_BIBR, XREF_BIBR The structural interface of the p53, Mdm2, and Mdm4 complex is characterized by an alpha-helix from the N-terminal transactivation domain of p53 which binds into a hydrophobic groove on the surface of the N-terminal domain of both Mdm2 and Mdm4."
32874502
reach
"In conclusion, Nutlin-3 fully destabilizes the p53, MDM2, and MDM4 complex and synergizes with cisplatin to intensify p53 function, which then downregulates Rad51 through a bimodal mechanism."
32063580
sparser
"This perhaps suggests that either MDM2–p53 or MDMX–p53 binding is not sufficient for complete p53 activity suppression, or that without E3 ligase-mediated degradation by MDM2, increased levels of p53 are also spontaneously more active."
28096294
sparser
"A detailed review of approaches targeting p53-MDM2-MDM4 interactions was provided by Wade et al. [ xref ]."
27916892
sparser
"These results indicate that MDM2 and MDMX can physically interact with p53 and p73α but not with p63α."
11223036
sparser
"As shown in xref , p53 has 393 amino acid residues that can be subdivided into five domains: the N-terminal transactivation domains (TAD) that are responsible for its binding to the p53-binding sites on MDM2 and MDMX, a proline-rich region (PP) that contains five PxxP motifs and is essential for inducing apoptosis, a DNA-binding domain (DBD), a tetramerization domain (TET), and a C-terminal domain (CTD) that is critical for the binding of p53 to the TRAF domain of USP7 ( xref ; xref )."
32300595
sparser
"Although transient transfection is widely used to study short-term effects in cellular functions [ xref , xref , xref ], the significance of the long-term effects of Mdm2 and MdmX RING domain on endogenous p53/Mdm2:MdmX remain to be tested in vivo."
32075226
sparser
"The interaction between p53 and MDM2 and MDMX involves the p53 transactivation domain (p53TD) and the N-terminal domains (NTD) of both MDM2 and MDMX."
35780910
sparser
"Disruption of the p53:MdmX/Mdm2 interaction through mutation, or inhibition by small molecules, stabilizes and activates p53 through reduced ubiquitination and 26S proteasomal degradation xref , xref ."
26812210
sparser
"In contrast, ATSP-7041 exhibited dose-responsive disruption of both the p53-HDM2 and p53-HDMX interactions, with no disruptive effect on BRCA1/BARD1 complex formation ( xref )."
27721413
sparser
"Stapled peptides are now reaching clinical trials, with one of the most advanced agents being ALRN-6924, an inhibitor of HDM2 and HDMX interaction with p53, having undergone phase I clinical trial ( xref )."
30689917
sparser
"MDM2 and MDMX bind to a short helical region of the tumor suppressor p53 and inhibit its function both directly, by blocking activation activity, and by promoting ubiquitination that leads to degradation."
27123812
sparser
"Chang et al. demonstrated that stapled α-helical peptide can be developed as an inhibitor of the interaction of p53 with MDMX and MDM2 (Chang et al., xref )."
30761293
sparser
"MDM2 and MDMX bind to p53 at their N-terminal domains to inhibit its transactivation."
29348869
sparser
"The disruption of MDM2-p53 and MDM4-p53 interactions is targeted through small molecular weight molecules, such as the nutlins, which are cis-imidazoline derivatives."
19707334
sparser
"Furthermore, compounds that inhibit both p53-Mdm2 and p53-MdmX binding have been generated and are being studied (RO-5963) ( xref )."
28690977
sparser
"Ser20 phosphorylation inhibits MDM2 and MDM4 binding to p53."
28031409
sparser
"They were also found to inhibit the p53-Mdm2 interaction with K i = 0.62 and 0.84 μM respectively, similar to the binding affinities for Mdmx, suggesting that pyrrolopyrimidines 36a and 36b act as dual inhibitors of Mdmx- and Mdm2-p53 interactions."
21623312
sparser
"The interactions of p53 with Mdm2 and MdmX are also modulated by posttranslational modifications (PTMs) of p53TAD including phosphorylation at S15, T18 and S20 that inhibits p53-Mdm2 binding."
30832340
sparser
"Of importance, since HAUSP contains a well-conserved catalytic core domain, it should therefore be a more tractable drug target than blocking the p53-MDM2-MDMX interaction."
22056774
sparser
"Upon DNA damage or a variety of cellular stresses, Mdm2/Mdmx:p53 interactions are inhibited and p53 is free to transcribe genes needed for cell cycle inhibition and/or apoptosis ( xref )."
27932484
sparser
"In contrast the RO-5963 compound, which is a potent inhibitor of both interactions of p53 with Mdm2 and Mdm4, exhibited no inhibition of either FLUOPPI PPI system after 1 hour of treatment."
31784573
sparser
"Therapies are being pursued to restabilize misfolded p53 or to abrogate the interaction of wild type p53 with negative regulators such as Mdm2 and/or Mdmx, which can be overexpressed [ xref , xref , xref , xref ]."
31795143
sparser
"Together, these data show that Mdmx F488A binds both p53 and Mdm2, and suggest that the dominant negative effect of Mdmx F488A is due to direct perturbation of Mdm2 ligase function, rather than sequestration of p53."
22266850
sparser
"In addition, the interaction between p53 and Mdm2 or MdmX suppresses the transcriptional activities of p53."
24691905
sparser
"Because the MDM2 C462A mutation not only disrupted MDM2-MDMX binding but also eliminated MDM2 E3 ligase function, we want to determine whether the MDM2 E3 ligase function might contribute to MDM2-p53 and MDMX-p53 binding."
33277368
sparser
"Using phosphomimetic mutations we investigated the effect of phosphorylation on the binding of p53 with Mdm2, MdmX, and CBP/KIX and the transient secondary structure of p53TAD."
30832340
sparser
"Both HDM2 and HDMX bind to p53 and prevent cell cycle arrest or apoptosis in damaged cells."
19880322
sparser
"The latter class represents cyclic peptides in β-sheet confirmation which inhibit the association of both MDM2 and MDMX with p53 [ xref ]."
24180275
sparser
"Although both MDM2 and MDM4 bind to p53 similarly through a hydrophobic pocket at their NTRs, the p53‐inhibiting activity of MDM4 (but not MDM2) is in turn inhibited by an MDM4 auto‐inhibitory sequence, located in the central region of MDM4 (Bista et al ., xref ; Chen et al ., xref )."
30672125
sparser
"Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use."
19255450
sparser
"The IC 50 s determined for VIP-82 SCRAM were approximately 6-fold and 12-fold higher against Mdm2, and 6-fold and 5-fold higher against Mdm4 than those derived with VIP-82 at both time-points, implying that the inhibitory effects on the Mdm2:p53 and Mdm4:p53 nanoBIT complexes are not a direct consequence of Mdm2/4 inhibition."
31784573
sparser
"We apply this technique to study binding of P53-derived peptides to MDM2 and MDMX."
28042966
sparser
"Like MDM2, MDMX also interacts with the transactivation domain of p53 through its highly conserved N-terminus and interferes with p53 transcriptional activity [ xref – xref ]."
23151129
sparser
"The small molecule RO-5963 has been reported to block both MDM2-p53 and MDMX-p53 interaction, thereby exerting high in vitro and in vivo efficacy against cancer cell lines and mouse xenografts that express high levels of MDMX."
27327543
sparser
"Also, both MDM2 and MDMX bind to p53 with similar affinity to block p53’s transcriptional activity ( xref )."
28118981
sparser
"The binding of MDM2 Y487A or MDMX to p53 appeared unaffected in the Mdm2 Y487A/Y487A ;Mdmx + / + ;p53 ER/- MEFs ( xref ), suggesting that the MDM2 E3 ligase activity is not required for MDM2-p53 binding, but rather the presence of the MDM2-MDMX physical interaction is important for p53 binding."
33277368
sparser
"For NAPA 25, each HPLC peak was separated and independently tested for inhibition of both HDM2 and HDMX binding to p53."
19880322
sparser
"Mdmx interacts with p53 and inhibits its transcriptional activity and its capacity to bind to Mdm2 and stabilize this protein may enhance the inhibition [54] ."
17512070
sparser
"A 12-mer dual inhibitor peptide (pDI) was previously reported to be able to target and inhibit MDMX:p53 and MDM2:p53 interactions with nanomolar potency in vitro."
27287767
sparser
"Mdm2 and mdm4 proteins form heterodimers that are much more effective in regulating p53 ( xref )."
35070964
sparser
"We hypothesized that the ability of MdmX to induce a sharp dependence of p53 activity on Mdm2 might be accounted for by the formation of MdmX∶p53 and Mdm2∶MdmX heterodimers."
20174603
reach
"To better understand differential stabilization and activation of p53 through DNA damage dependent regulation of the p53, MDM2, and MDM4 complex by the specific platinum drugs requires an examination of the role of post-translational modification."
28031409
sparser
"The obtained computational results suggest that the compound 3a can act as a dual inhibitor of MDM2-p53 and MDMX-p53 interactions, consistent with the experimental results."
21820342
reach
"Our results demonstrate that Nutlin-3, but not RITA, effectively disrupted the p53, MDM2, and MDM4 complex to activate p53, which increased robustly with cisplatin and Nutlin -3 combination and enhanced antitumor effects than either agent alone."
32063580
sparser
"More recently, indolyl-hydantoin derivatives were reported to potently block p53 binding with both MDM2 and MDMX."
27187415
sparser
"Studies have shown that reactivation of wild‐type (wt) TP53 by inhibiting MDM2‐p53 interaction or knockdown of MDM2 and MDM4 induces cell cycle arrest and apoptotic cell death, inhibiting tumor growth in tumors carrying wt TP53 . xref , xref , xref , xref , xref , xref , xref , xref Thus, MDM2 and MDM4 are ideal targets for cancer therapy in such tumors."
30488540
sparser
"While we cannot exclude the possibility that CDKIs inhibit the expression of other E3s for p53, this variability could also stem from the extreme complexity of the network of physical and functional interactions between MDM2, MDM4, and p53, including several feedback loops."
32934219
sparser
"In the presence of MDMX ΔRING , MDM2 E3 ligase activity appears to remain intact in MEFs ( xref ), suggesting that MDM2-mediated ubiquitination of p53 and MDM2–p53 or MDMX–p53 binding in the absence of heterodimer formation is not sufficient to permit embryonic development."
28096294
sparser
"P53, MDMX and MDM2 form a highly dynamic regulatory node that contains positive and negative feedback loops ( xref )."
30319942
sparser
"Our results provide biochemical evidence on the dynamics of the p53-Mdm2-Mdm4 interactions in affecting p53 levels and activity, and unlike previously reported findings derived from genetically manipulated systems, AML cells with naturally high levels of Mdm4 remain sensitive to nutlin treatment."
24659749
sparser
"When LNCaP and 22Rv1 cells, two prostate cancer cell lines carrying the wild-type copy of the TP53 gene, were treated with the dual inhibitor RO, or with a combination of nutlin-3 and SJ, p53 was stabilized and activated, since both treatments disrupted the p53 interaction with MDM2 and MDMX."
29464071
sparser
"To evaluate the feasibility and biological effects of simultaneously disrupting p53 binding to MDM2 and MDMX, we used phage display to identify a novel peptide that can inhibit p53 interactions with MDM2 (IC(50) = 10 nmol/L) and MDMX (IC(50) = 100 nmol/L)."
17875722
sparser
"Mdmx F488A binds Mdm2 and p53, but reduces p53 ubiquitylation."
22266850
sparser
"Previously, PDI was determined to inhibit the full-length p53 binding to Mdm2 and Mdmx with IC 50 values of 44 nM and 550 nM, respectively, in an ELISA assay. xref To gauge the effect of stapling on inhibitory activity, stapled PDI analogs 1-3 were evaluated and their inhibitory activity data were collected in xref ."
21277201
sparser
"Phosphorylation of T18 leads to a 19–22-fold reduction in binding affinity of p53TAD to Mdm2, and one study has described an equivalent effect of phosphorylated T18 on Mdm2 and MdmX binding to p53 [ xref , xref , xref ]."
30832340
sparser
"ATSP-7041 is a progenitor of the clinical compound ALRN-6924 that specifically binds to and inhibits both major p53 regulators, MDM2 and MDM4 xref ."
33536467
reach
"Next, given that FAM193A interacts with MDM4 and that FAM193A depletion deregulates p53, MDM4, and MDM2 protein levels, we evaluated whether formation of the p53/MDM2/MDM4 complex is affected by FAM193A ablation."
36897777
sparser
"In unstressed cells, p53 interacts with Mdm2 and MdmX, which inactivate p53, and ubiquitinate it activating the proteasome-mediated degradation, keeping p53 at a low level ( xref )."
33015052
reach
"Since tumor models derived from A2780 cells are used in drug development studies, it becomes important to determine whether novel drugs arising from such studies are achieving their desired goals of circumventing cisplatin resistance by effectively disrupting the p53, MDM2, and MDM4 complex."
26876197
sparser
"Thus, this FP assay can be used for identification of small molecule inhibitors that disrupt the MDM2-p53 or MDMX-p53 interactions in vitro."
23150440
sparser
"PMI competes with p53 for MDM2 and MDMX binding at an affinity roughly 2 orders of magnitude higher than that of (17-28)p53 (ETFSDLWKLLPE) of the same length; both peptides adopt nearly identical alpha-helical conformations in the complexes, where the three highlighted hydrophobic residues Phe, Trp, and Leu dominate PMI or (17-28)p53 binding to MDM2 and MDMX."
20226197
sparser
"Importantly, the precise amino acids that are essential for the interactions of the p53 TAD with both MDM2 and MDMX are identical ( xref ), leading to the development of dual inhibitors of p53-MDM2/MDMX interactions ( xref – xref )."
32850448
sparser
"A structure-based approach led to identification of nutlin-3a (2-piperazinone, 4-[(4 S ,5 R )-4,5-bis(4-chlorophenyl)-4,5-dihydro- 2-[4 methoxy-2-(1-methylethoxy)phenyl]-1 H –imidazol-1-yl]carbonyl]-) ( xref ), a small molecule that inhibits the MDM2-p53 interaction by binding the p53 binding pocket of MDM2.[ xref ]Nutlin-3a also binds MDMX and prevents the association of both MDM2 and MDMX with p53[ xref , xref ]( xref )."
26202204
sparser
"P53 can be acetylated by the histone acetyltransferase CBP/p300 and p300/CBP associated factor (PCAF) at K320 [ xref , xref ], K164 [ xref ] or C-terminal domain (K370, 372, 373 and K382) [ xref ], which blocks Mdm2 and Mdmx binding to p53, thus preventing degradation of p53 and promoting the recruitment of p53 to target promoters."
25544752
sparser
"MDMX binds to both MDM2 (Sharp et al., xref ) and p53 (Shvarts et al., xref )."
23565502
sparser
"Progress has also been made in the development of stapled peptides, such as ALRN-6924, that inhibit both MDM2-p53 and MDM4-p53 interaction, which are under (pre-)clinical evaluation for hematological malignancies (NCT02264613) [ xref , xref ]."
33260693
sparser
"One of the promising strategies to treat cancers with wtp53 is to apply dual inhibitors of MDM2-p53 and MDMX-p53 interactions [ xref ]."
32971841
sparser
"Discovery of MDM2-p53 and MDM4-p53 protein-protein interactions small molecule dual inhibitors."
35961068
sparser
"Optimization to inhibit HDM2 and HDMX Binding to p53."
19880322
sparser
"For tumors with elevated levels of MDM2 or MDMX and wild type p53, it may be possible to induce p53-mediated cell death by disrupting the MDM2-p53 or MDMX-p53 interaction."
22675482
sparser
"This has led to the discovery of a list of potent Mdm2–p53 inhibitors xref with several compounds of this class being advanced to phase I clinical trials in hematological neoplasia and solid tumors. xref However, the therapeutic effects of these Mdm2–p53 inhibitors can be attenuated by MdmX overexpression. xref , xref , xref Although peptide inhibitors with dual functions of inhibiting both Mdm2–p53 and MdmX–p53 interactions will overcome this problem and enhance p53-dependent cancer killing; xref , xref these inhibitors will not inhibit Mdm2 E3 ligase activity toward non-p53 targets such as retinoblastoma protein (RB), p21 and DAXX (death domain-associated protein), xref , xref , xref which to a different extent contributes to the p53-dependent biological effects."
26720344
sparser
"Designing inhibitors that block p53 interactions with both MDM2 and MDMX has proven difficult due to the differences in p53 binding sites."
23151129
sparser
"Here are several small molecule compounds and stapled peptides which can inhibit the interaction between P53 and MDM2 or P53 and MDM4."
33854378
sparser
"In addition, we have identified potent, dual inhibitors of MDMX- and MDM2-p53 interactions through high-throughput screening, highlighting that they can serve as α-helix mimetics ( xref , xref and xref )."
21171592
sparser
"MdmX interacts with p53 or Mdm2 to form transcriptionally inactive p53∶MdmX or enzymatically inactive Mdm2∶MdmX."
20174603
sparser
"Nutlin binds to MDM2 versus MDMX with a 40-fold stronger inhibition constant ( K i of 0.7 versus 28  μ M), whereas MDMX and MDM2 bind to p53 with similar affinities ( K d =0.5  μ M). xref , xref Thus, in the presence of Nutlin, MDMX is still able to bind to p53 and repress its transcriptional activity. xref , xref Consequently, knockdown of MDMX was reported to potentiate Nutlin-induced apoptosis. xref , xref , xref We confirmed these findings."
21562588
sparser
"The interactions of p53 with Mdm2 and Mdmx, mediated via the TA domain of p53 have been well-documented ( xref ; xref ; xref ; xref )."
25201187
sparser
"We added 10% fetal bovine serum (FBS) into the lysate BiLC assays to determine directly whether serum reduces the ability of stapled peptides to disrupt p53-Mdm2 and p53-Mdm4 interactions."
25464845
sparser
"An alternative independent strategy for mitochondria-targeted radiation mitigation was tested using a small molecule inhibitor of p53 binding to mdm2 and mdm4 ( xref – xref ), with the goal to enhance the bioavailability of p53 and enhance cellular repair processes ( xref , xref )."
21493014
sparser
"In particular, studies inhibiting the interaction of p53 with its negative regulators MDMX and MDM2 are an important field in drug discovery."
28281901
sparser
"Triarylpyrroles e.g. 4c and 4s inhibit the MDM2–p53 and MDMX–p53 protein–protein interactions."
24078862
sparser
"The IC 50 values for p53(15–29) binding to HDM2 and HDMX were 1–2 μ M. For Nutlin-3a the IC 50 values were 1 μ M and 6–7 μ M for HDM2 and HDMX, respectively."
19880322
sparser
"Out of these 15 entries, 14 entries are anti-cancer PPI targets, namely: eight related structures of MDM2 and MDMX bound to p53 and short peptides; five related structures of CDK4 bound to cyclin D1 and cyclin D3; and one structure of Smad4 bound to Ski."
20525787
reach
"In the present study, however, we have uncovered a novel mechanism of p53 inactivation for inducing cisplatin resistance whereby the heterozygous V172F missense mutation in p53 enhances MDM4 recruitment into the p53, MDM2, and MDM4 complex that prevents p53 dependent transcriptional activity and apoptosis."
26876197
sparser
"They potently block p53 binding with both HDM2 and HDMX by driving homo- and/or heterodimerization of HDM2 and HDMX proteins."
23822887
sparser
"While MDM2 and MDMX interacted with p53 in the absence of each other, they bound p53 more efficiently as a heterodimer."
33277368
sparser
"MDM2 and MDMX bind p53 and inhibit its function by distinct nonredundant mechanisms."
20080970
sparser
"The binding of both Mdm2 and Mdmx to p53 also directly inhibits p53 transactivation function by preventing recruitment of transcriptional co-activators ( xref )."
22266850
sparser
"Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions."
25388787
sparser
"Peptide inhibition of the interactions between p53 and its negative regulators MDM2 and MDMX could activate p53 both in vitro and in vivo , representing a viable and potent therapeutic strategy for cancer treatment."
36185610
sparser
"For example, two recently developed p53 inhibitors are predicated on disrupting the interaction between functional p53 and the p53 modifiers, MDM2 and MDM4 ( xref ; xref )."
22975378
sparser
"MDM2 and MDM4 interact directly with p53 to inhibit its transcriptional activity and promote its relocation to the cytoplasm."
32787886
sparser
"Consistent with the observation that both Mdm2 and Mdmx proteins interact with p53, the amino acids of Hdm2 required for the interaction with p53 [15] are strictly conserved in Hdmx."
15865931
sparser
"Given the therapeutic potential of selective HDMX targeting and the use of such agents as chemical probes and diagnostics of HDMX dependency, we sought to investigate distinguishing features of the HDM2 and HDMX p53-binding pockets that could inform the development of selective HDMX inhibitors."
32359398
sparser
"Crystal structure studies are needed to further understand at the molecular level how exactly the Mdm2-MdmX-p53 ternary complex is formed and why the Mdm2-MdmX complex is a more efficient E3 ligase complex than Mdm2 alone."
22410433
sparser
"Both MDM2 and MDMX bind to the transactivation domain of p53 with similar affinities to directly inhibit its transcriptional activity ( xref )."
28118981
sparser
"By subsequent dose-dependent validation experiments with these compounds, we verified the top three hits, denoted as LH1, 2, and 5, which acted as dual inhibitors of MDMX- and MDM2-p53 interactions at Ki values lower than 3 μM (see xref )."
23150440
sparser
"Disruption of the p53:MdmX/Mdm2 interaction through mutation or inhibition by small molecules stabilizes and activates p53 through reduced ubiquitination and 26S proteasomal degradation ."
26812210
sparser
"In this present study, we obtain insights into the role of phosphorylation in modulating interactions of p53 with Mdm2, MdmX, and CBP/KIX and the effect of phosphorylation on transient secondary structure."
30832340
sparser
"Immunoprecipitates indicated that ectopic wild-type p53 bound both MDM2 and MDM4, but this binding to p53-S20A mutant was relatively greater."
28031409
sparser
"MDM4 also interacts with MDM2 directly [ xref , xref ] to enhance MDM2-mediated ubiquitination and p53 degradation [ xref ]."
28430625
sparser
"PLISA confirmed that Mdmx F488A binds endogenous Mdm2 and p53 in intact cells ( xref )."
22266850
sparser
"MDM2 and MDMX bind to p53 via N-terminal p53-binding domains to control the level of p53."
27373663
sparser
"Regarding the different approaches to reactivate p53, whenever this protein is found as awild type in tumors and the p53-regulatory pathways are defective, the approach to its reactivation is the use of small molecules or peptides to inhibit the N-terminal interaction between p53 and MDM2 or MDM4."
27897991
reach
"Thus, the F15 formulation allowed sufficient esophageal uptake of the p53, Mdm2, and Mdm4 complex inhibitor BEB55, resulting in more free p53."
22021675
sparser
"Chemotherapeutic drugs that induce p53 as well as small molecules that disrupt the interaction between p53 and MDM2 or MDMX have been shown to induce cell death in prostate cancer cells [ xref – xref ]."
29464071
sparser
"We demonstrated that under physiological conditions although both MDM2 and MDMX can bind p53 by themselves, the MDM2-MDMX heterodimer binds p53 more efficiently than either individual protein ( xref )."
33277368
sparser
"The subsequent fluorescent polarization assay identified several compounds that inhibited MDM2-p53 and MDMX-p53 interactions."
23726030
sparser
"MDM2 and MDMX interact to form a heterodimer ( xref ), which is thought to promote more efficient p53 inhibition."
28096294
sparser
"Although the N‐terminal region (NTR) of both MDM2 and MDM4 bind similarly to p53 to inhibit p53‐mediated transactivation, the p53‐binding activity of MDM4 (but not MDM2) is inhibited by an intramolecular sequence, located in the central region of MDM4 (Bista et al ., xref ; Chen et al ., xref )."
30672125
sparser
"Inhibitors of the wt-p53/Mdm2 and wt-p53/MdmX Interactions."
32630327
sparser
"Like MDM2, MDMX interacts with the N-terminal region of p53 and partially inhibits p53 transcriptional activity."
10218570
sparser
"In order to model the interactions of MdmX with Mdm2 and p53, we selected a system of elementary processes that focused on the non-enzymatic interactions between MdmX and other molecules."
20174603
sparser
"Developing a strategy to simultaneously prevent the binding of both HDM2 and HDMX to p53 is an essential feature of inhibitors to restore p53 activity in a number of different cancers."
19880322
sparser
"In these studies we have developed a bimodal fluorescence foci PPI (FLUOPPI) based assay to measure the integrity of the interaction of p53 with both Mdm2 and Mdm4 in live cells."
31784573
sparser
"To develop an assay to simultaneously measure the interactions of both Mdm2 and Mdm4 with p53, a bimodal fluorescent based method was developed that utilised two different fluorescently tetramerizing tags (FP-tag), AG (Azami Green) with the Mdm2:p53 interaction and MR (Monti Red) with the Mdm4:p53 interaction."
31784573
sparser
"Many of the remaining tumors contain alterations that lead to over-expression of either of two oncogenes, Mdm2 or Mdm4 that bind to wild type p53 and inactivate it by serving as an E3 ubiquitin ligase (Mdm2) and/or a transcriptional repressor (Mdm2 and Mdm4)."
25464845
sparser
"The p53 protein binds to MDM2 and MDMX using a short helix with a “hot spot triad” consisting of p53’s Trp23, Leu26, and Phe19 [ xref ]."
25942498
sparser
"MDM2 and MDMX share considerable structural homology, binding to the N-terminus of p53 and leading to its transcriptional activity inhibition and degradation. xref Recent findings suggest that overexpression of MDM2 and MDMX is a key factor that results in multiple human cancers, making them the promising target for antitumor drug development. xref , xref – xref Hence, p53–MDM2 and p53–MDMX protein–protein interactions were selected as the model applications to evaluate the feasibility and practicality of our new developed foldamer."
33140956
sparser
"Peptide antagonists of p53–MDM2 and p53–MDMX interactions have been developed using structure-based rational design and phage display methods xref – xref ."
23303139
sparser
"SAH-p53-8, whose uptake is impeded by 10% serum conditions, showed modest activity against the p53-HDM2 and p53-HDMX interactions at the higher 20 μM dose level with no effect on BRCA1/BARD1 ( xref ), whereas Staplin disrupted only the p53/HDM2 interaction (in non-dose-responsive fashion), with no effect on p53/HDMX or BRCA1/BARD1 ( xref )."
27721413
sparser
"In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein."
32101134
sparser
"To assess the ability of PhR to inhibit p53 binding to MDM2 and MDMX, we incubated with PA-1 cells with PhR at 40 μM for 4 h and determined the levels of MDM2 and MDMX associated with p53 by immunoprecipitation (IP) from cell lysates followed by western blotting."
29158845
sparser
"ALRN-6924 is the newest stapled peptide that binds equally to MDM2 and MDMX and disrupts both MDM2–p53 and MDMX–p53 interactions."
27327543
sparser
"In contrast, activation of AKT kinase function in cancer stabilizes MDM2 and MDM4 interactions resulting in inhibition of p53 activity [ xref , xref ]."
25152696
sparser
"The interactions between p53 and MDM2 or MDMX are mediated mainly by three key residues (Phe19, Trp23, and Leu26) of p53 and the hydrophobic pocket in the N-terminal domain of MDM2 or of MDMX ( xref – xref )."
23150440
reach
"Positively charged cell-permeable stapled peptides have also been shown to inhibit the p53, Mdm2, and Mdmx complex [XREF_BIBR]."
27898034
sparser
"These results suggest that the compounds act as dual inhibitors of MDMX- and MDM2-p53 interactions."
21171592
sparser
"Importantly, the C-terminal residue Pro of PMI induced the formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX [ xref ]."
25201201
reach
"Diverse signaling pathways converge on the p53, MDM2, and MDM4 complex to release p53 from its repressors and enable it to regulate transcription of downstream target genes involved in cellular responses such as cell cycle arrest, apoptosis, senescence, autophagy, DNA repair and central metabolism."
24867637
sparser
"An optimized NAPA was able to equally inhibit the association of both HDM2 and HDMX with p53."
19880322
sparser
"In this report we describe the development of a Flu orescent P rotein- P rotein I nteraction-visualization (FLUOPPI) to enable the simultaneous measurement of both Mdm2:p53 and Mdm4:p53 interactions in order to assess the relative efficiencies of mimetic molecules of the p53 peptide helix against both PPIs."
31784573
sparser
"From this study, the best NAPA for inhibition of HDM2 and HDMX binding to p53 is the one represented by entry 25."
19880322
sparser
"P53 activity is suppressed in mice until post-implantation development by virtue of the interaction between p53 and MDM2, MDM4 and PACT/RBBP6 [ xref , xref ]."
| PMC
reach
"Transcriptional activity of p53 is inhibited by its binding to Mdm2 and Mdm4, but is essential for its function, which is affected via post-translational phosphorylations that disrupt the Mdm2, Mdm4, and p53 complex and release p53 [XREF_BIBR]."
28038466
sparser
"These results indicate that wild-type p53 upregulation associated with downregulation of MDM2 and MDMX can also play a dominant role in the killing of tumour cells by SF3B1 inhibition and that there may be a level of tumour selectivity because of the greater sensitivity of MDM2/MDMX expression in transformed cells."
29796170
sparser
"This observation could reflect an ability of the bivalent peptide to mimic p53AD-Mediator binding to activate transcription (as suggested in vitro for the BP1.4 peptide; xref ) and/or an ability to reduce MDM2 or MDM4 binding to p53 in HCT116 cells."
35385747
sparser
"In cells with a high level of stress, the interactions between MDM2, MDM4, and p53 are disrupted, allowing activated p53 to exert its transcriptional activity."
20420946
sparser
"Using a battery of biochemical and biophysical tools, we found that retro-inverso isomerization diminished p53 (15-29) binding to MDM2 or MDMX by 3.2-3.3 kcal/mol."
20382735
sparser
"Therefore, availability of drugs that interfere with p53-Mdm2 and p53-Mdm4 interactions could restore p53 function and significantly benefit patients whose cancers express wild type p53 ( xref ; xref )."
25464845
sparser
"Both Mdm2 and Mdm4 bind to the p53 transactivation domain with similar affinities; therefore, they may compete for the binding and inhibition of p53 activity."
23327795
sparser
"Accordingly, amplification of two oncogenes associated with p53 regulation, MDM2 , and MDM4 , as well as polymorphisms in these genes have been associated with RB development and/or survival (Laurie et al., xref ; de Oliveira Reis et al., xref )."
23233862
sparser
"Taking into account the well-known structure of the MDM2-p53 complex, and the fact that the inhibition of the wild-type (wt) p53 via p53/MDM2/MDMX axis is essential for cancer to develop (reviewed in [ xref ]), inhibition of the MDM2-p53 and MDMX-p53 interactions has become a very promising strategy for cancer therapy and is described in more detail below."
32971841
sparser
"For example, mouse knock-out studies showed that the Mdm4 -knockout mice results in p53-dependent embryonic lethality with defects in proliferation and no apoptosis, which were rescued by knocking out the p53 gene, suggesting the biological role of the p53–MDM2–MDM4 interaction and the major function of these molecules during embryonic development [ xref – xref ]."
28099948
sparser
"Several compounds and peptides have been described that block the interaction of p53 with MDM2 and/or MDMX [ xref , xref – xref ]."
27327543
sparser
"We next determined whether the ability of SAH peptide-based antagonists that have been shown to disrupt p53-Mdm2 and p53-Mdm4 interactions in vitro do so in living cells."
25464845
sparser
"Nutlin-3 disrupts both MDM2-p53 and MDM4-p53 interactions in retinoblastomas with less efficiency in the latter."
32824373
sparser
"MDM2 serves as an E3 ubiquitin ligase to degrade p53, and MDM2 and MDM4 together bind to the transcriptional activation domains of p53 to inhibit its transactivation function. xref Furthermore, consistent with the predictions, a significant increase in the apoptosis of normal cells was observed in an acid-dependent manner."
32322666
sparser
"Accumulating evidence indicates that Mdmx interacts with both p53 and Mdm2 and that the activities of Mdmx are intimately linked with either p53 or Mdm2 in human cancer cells ( xref , xref )."
29523541
sparser
"To overcome this limitation, we developed &quot;angler peptides&quot; by conjugating KD3, a noncell permeable but potent and specific peptide inhibitor of p53:MDM2 and p53:MDMX interactions, with a set of cyclic cell-penetrating peptides."
33533253
sparser
"HDMX is physically associated with HDM2 and drugs that block the interaction between HDM2 and p53 such as MI-319 also interfere to some extent with the ability of HDMX to suppress p53 transcriptional activity."
23497256
sparser
"If Mdm2 and MdmX are associated with p53, they should co-elute with p53 from sucrose gradients."
25719246
sparser
"Like USP2a, USP7 is involved in the complex regulation of the p53 tumor suppressor through its interactions with p53, Mdm2 and Mdmx."
18687060
sparser
"The restoration of the impaired function of the p53 protein by disrupting the Mdm2–p53 or Mdmx–p53 interaction offers a fundamentally new avenue for the treatment of a broad spectrum of cancers.[ xref – xref , xref ]Cancer cells have been shown to be extremely sensitive to the restoration of p53 function, verifying the expectation of highly effective therapies from this approach.[ xref ]Many currently used genotoxic chemotherapeutics rely on DNA-damage-dependent activation of p53 to mount an apoptotic response."
21341346
sparser
"We have successfully demonstrated that the dual FLUOPPI PPI system can accurately measure the effects of Mdm2 specific (Nutlin 3A, MI-773) and bispecific (RO-5963) small molecule inhibitors on the p53:Mdm2 and p53:Mdm4 interactions pairs, respectively."
31784573
sparser
"Towards this end, a great deal of work has been devoted to the development of compounds that either interfere with the p53-MDM2 and p53-MDMX interactions, inhibit MDM2 E3 activity, or target individual DUBs."
23151129
sparser
"Although the RING domain of Mdm4 is not enzymatically active, both Mdm2 and Mdm4 bind to the N-terminal transcriptional activation domain of p53 and repress the transcriptional activity of p53 in homoeostasis."
28093454
sparser
"Although most of the screening against the MDM2/MDMX-p53 interaction have been based on biochemical and biophysical assays as discussed above, a high-affinity peptide inhibitor of p53 interaction with MDM2 and MDMX was also identified by screening a duodecimal peptide library displayed on M13 phage using site-specific biotinylated p53-binding domains of human MDM2 and MDMX [ xref ]."
25201201
sparser
"ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin."
29789628
sparser
"We evaluated the specificity of ReBiL for studying p53-Mdm2 interaction with their antagonist Nutlin-3a, which is known to disrupt p53-Mdm2 but not p53-Mdm4 interactions ( xref ; xref ; xref )."
25464845
sparser
"A separate class of inhibitors of p53-Mdm2 and p53-MdmX binding are the stabilized small peptides termed “stapled peptides” ( xref , xref )."
28690977
sparser
"We use the Mdm2-p53 and MdmX-p53 interactions [ xref , xref ] as proof-of-concept systems to develop our protocol and use the method on the immune oncology system of the PD-1/PD-L1 interaction [ xref , xref ]."
32630327
sparser
"In contrast, SJ057 may inhibit interactions between p53 and both Mdm2 and MdmX to activate p21 expression."
26812210
sparser
"After several rounds of optimization, a single trimeric inhibitor was developed that equally inhibits HDM2 and HDMX binding to p53 with IC 50 values in the low micromolar range."
19880322
sparser
"A great challenge in the PPI of cancer is to identify the subtle differences between how MDM2 and MDM4 bind to p53."
28837642
reach
"DNA damage by cis-Pt or carboplatin upregulates key cellular pathways to stabilize p53 by dissociating the Mdm2, Mdm4, and p53 complex, thereby allowing p53 to translocate to the nucleus, where it binds to specific DNA sequences for transactivation of target genes, exemplified by p21, Mdm2 and Bax [XREF_BIBR - XREF_BIBR]."
28038466
sparser
"Measurement and quantitative assessment of the interactions of p53 with Mdm2 and Mdm4."
31784573
sparser
"The detrimental effect of the phosphorylation of p53 Thr18 ( xref ), p53 Ser20 ( xref ), MDM2 Ser17 ( xref ), and MDMX Tyr99 ( xref ) on p53 binding to MDM2 or MDMX have also been extensively studied in MD and Brownian dynamics (BD) simulations."
30726928
sparser
"At least two pathways have been identified by our previous studies and other groups, through which the interaction between p53 and MDM2 or MDMX can be blocked."
28118981
sparser
"Phosphorylation at Ser15 inhibits the interaction of p53 with its antagonists MDM2 or MDMX, which de-stabilize p53 and inhibit apoptosis."
28438385
sparser
"Furthermore, the stabilized p53 can be reactivated by attenuation of the interaction of p53 with either Mdm2 or Mdmx."
22266850
sparser
"Recent studies showed that disrupting p53-MDM2 and p53-MDMX interactions can lead to robust activation of p53 but also revealed a need to develop novel dual specific or MDMX-specific inhibitors."
19910468
sparser
"We then evaluated a second compound, RO-5963, that has been proposed to disrupt both p53-Mdm2 and p53-Mdm4 interactions by increasing Mdm2-Mdm4 association ( xref )."
25464845
sparser
"P53 binding to MDM2 and MDM4 heterodimer strictly controls its function in normal cells [ xref , xref ]."
31995625
sparser
"Graves and coworkers at Roche Research Center instead identified a class of small molecules that inhibit both p53–MDM2 and p53–MDMX binding by inducing MDM2–MDMX protein dimerization, occluding the p53 binding site (Graves et al., xref )."
26380257
sparser
"In a study by Chang et al. , the authors describe a stapled α-helical peptide that binds to the p53-binding domains of MDM2 and MDMX with low-nanomolar affinities. xref Although controversial, stapled peptide technology offers the unique opportunity to specifically mimic the p53-binding site in MDM2 and/or MDMX with strong affinity."
27041565
sparser
"MDM4 not only interacts with MDM2 and p53, but it is also an essential p53 antagonist in vivo [ xref ]."
35053170
sparser
"Inhibition of the interaction between the tumor suppressor protein p53 and its negative regulators MDM2 and MDMX is of great interest in cancer biology and drug design."
20226197
sparser
"Despite adequate bioavailability and pharmacokinetic profiles, these small inhibitors suffer from lack of targeting specificity and inefficient simultaneous inhibition of both p53-MDM2 and p53-MDM4 interactions."
20822110
sparser
"In this study, we show that bicyclic β-proline oligomer derivatives inhibit p53-MDM2 and p53-MDMX protein-protein interactions, exhibiting MDM2-antagonistic and MDMX-antagonistic activities."
31582633
sparser
"The interaction between MDM2 and MDM4 is essential for E3 ligase activity of MDM2 and, thereby, inducing proteosomal degradation of p53 and maintaining its levels below a critical threshold for activity. xref , xref Moreover, the qualitative nature of negative regulation of p53 is dependent on MDM2 and MDM4 levels, with relatively greater levels of MDM4 inhibiting MDM2-mediated p53 degradation and/or competing with MDM2 for the p53 binding site to inhibit its transcription activity. xref , xref DNA damage signals, however, can inhibit interaction between p53 and MDM2 or MDM4, and accelerate MDM4 degradation by MDM2, to stabilize and transcriptionally activate p53. xref – xref "
26876197
sparser
"MDM2 or MDM4 gene amplification is only associated with the wild-type TP53 gene in retinoblastomas, thus the amplification of the two genes is mutually exclusive."
21503588
sparser
"In both Mdm2 and MdmX complexes with p53, the side chains of Leu22 and Leu26 were pointing to the outside of the main pocket occupied by Trp23 and Phe19 and had little effect on the structural arrangements of the p53-binding pockets of Mdm2/X, making them ideal candidates for our w-AIDA assay [ xref , xref , xref ] ( xref a,b and xref )."
32630327
sparser
"MDM2 and MDM4 interact with the N-terminal transactivation domain of p53, thereby negatively regulating p53 [17–19] ."
19631207
sparser
"The protein protein interaction of the transcription factor p53 and its negative regulator MDM2 and MDMX is a highly competitive field in drug discovery with one compound in early clinical development and several compounds in the preparation to enter clinical evaluation in cancer."
22650254
sparser
"Mdm2 and MdmX binding to p53 restrain p53 transcriptional activity and keep p53 in the non-active un-acetylated form."
25433195
sparser
"It is hypothesized that targeting TP53 interactions with MDM2 and MDMx will have a more significant impact than MDM2 inhibition alone."
31289443
sparser
"For example, interactions between p53 and its negative regulators MDM2 and MDM4 occur primarily through TAD1 ( xref – xref ), while interactions with RPA and the p62 subunit of TFIIH occur through TAD2 ( xref – xref )."
19166313
sparser
"These hybrid peptides inhibit p53-MDM2 and p53-MDMX protein-protein interactions."
31518151
sparser
"The mechanism of action of BEB55 may be through its direct inhibition of the interaction of Mdm2 and Mdm4 with p53 [ xref ]."
23933481
sparser
"Multiple studies demonstrate that MDMx:MDM2 heterodimers bind and ubiquitinate p53, targeting p53 for degradation by the proteasome, and thus, allowing cells to maintain a low basal level of this pro-apoptotic protein under normal conditions ( xref )."
24128662
sparser
"The stability and activity of p53 is regulated primarily through the modulation of the interaction between p53 and its negative regulators Mdm2 or MdmX, which suppress the transcriptional activities of p53 (ref. xref )."
20818388
sparser
"The majority of these prevent the interaction of MDMX and/or MDM2 with p53."
29796170
sparser
"Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins."
22745160
sparser
"We found from in silico screening and confirmed by experiment that lithocholic acid (LCA) binds to the p53 binding sites of both MDM2 and MDM4 with a fivefold preference for MDM4."
23035244
sparser
"ALRN-6924 (Aileron Therapeutics) belongs to a different class of therapeutics, which are stapled peptides designed to disrupt p53 interaction with both MDM2 and MDMX."
26858935
sparser
"Additionally, it has been reported that ALRN-6924, a staple peptide that blocks binding of MDM2 and MDM4 to TP53, was effective for TP53-wild type PTCL cases and acute myeloid leukemia [ xref , xref ]."
33918793
sparser
"According to the above analysis, MDM2 can form more hydrogen bonds than MDMX with p53."
30761293
sparser
"However, recent data raise questions about the ability of some SAH peptides to interfere with p53-Mdm2 and p53-Mdm4 interactions in cells ( xref )."
25464845
sparser
"Interestingly, the PRD has different consequences between the interaction with MDM2 and MDM4, an MDM2-related protein and p53 negative regulator [ xref ]."
33932560
sparser
"Additionally, the principles correctly predict the essential bound waters in HIV Protease, the surprisingly extensive binding site of elastase, the pinpoint location of electron transfer in dihydrofolate reductase, the HIV TAT-TAR protein-RNA interactions, and the MDM2-MDM4 differential binding to p53."
28837642
sparser
"Understanding the context of Mdm-2-p53 and Mdm4-p53 interactions, and the development of small molecules that also inhibit Mdm4 or cause dual inhibition of Mdm2 and Mdm4 [ xref , xref ], will be critical to optimize Mdm-targeting therapies for clinical use."
22239435
sparser
"Despite previous study that showed that p14ARF also bind to both MDM2 and MDMX, we identified no peptide sequences that were similar to p14ARF, indicating that p53-derived peptides are more suitable for inhibiting MDM2- and MDMX-p53 interaction than that of p14ARF."
21423613
sparser
"Most MDM2/MDMX-targeted agents disrupt p53–MDM2 or p53–MDMX interaction or inhibit MDM2 ubiquitin ligase activity [ xref , xref ]."
25547493
sparser
"Both MDM2 and MDMX bind the p53 transactivation domain through their N terminus( xref ), but the p53 binding efficiency by either protein alone had not been determined under physiological conditions."
33277368
sparser
"The effect of this new chemical library on p53–MDM2 and p53–MDMX interactions was thereafter investigated, using the reported yeast‐based screening assay (Soares et al ., xref )."
28296148
sparser
"Under normal conditions, p53 is negatively regulated by MDM2 or MDM4, which bind the TAD domain of p53, inducing the degradation of the protein by ubiquitination [ xref , xref ]."
29510549
sparser
"Joseph et al . carried out MD simulations to differentiate binding of p53 and nutilin to MDM2 and MDMX. xref They showed that apo-MDMX has lower flexibility than apo-MDM2, based on the principle component analysis using MD trajectories."
22731511
sparser
"Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions."
35720128
sparser
"Given that the proteins encoded by these mRNAs retain the ability to interact with either full length Mdm2, Mdmx or p53, they may also influence the response to Mdm2/Mdmx antagonists."
19147532
sparser
"Elucidating the molecular basis for peptide inhibition of p53 interactions with MDM2 and MDMX is important for the design of p53 activators for therapeutic applications."
20226197
sparser
"Another intriguing question that arises from the interaction of p53 with Mdm2 and MdmX on gene promoters is whether p53 can be ubiquitinated by Mdm2 while bound to DNA and what role phosphorylation may play in regulating the p53 interaction with Mdm2 and MdmX when p53 is bound to DNA."
19450511
sparser
"Both MDM2 and MDM4 can directly interact with the N-terminal domain of p53 and inhibit the transactivation of target genes xref , xref , xref ."
32934219
sparser
"Similarly, the stapled p53 peptide bound to MDM2 and MDMX roughly one order of magnitude stronger than 16–27 p53 ( xref and Fig. S3 xref )."
30809370
sparser
"However, inhibition of either the p53–MDM2 or p53–MDMX interaction alone was not sufficient to fully restore p53 signaling, and simultaneous inhibition of both PPIs is necessary for full activity (Tovar et al., xref ; Brown et al., xref )."
26380257
sparser
"Overexpression of Mdm4 in tumours has been demonstrated to compromise the efficiency of Mdm2 specific compounds, presumably through the maintenance of heterodimeric complexes of Mdm2 and Mdm4 that inhibit and target p53 for proteosomal degradation xref ."
31784573
sparser
"The MDMX-MDM2-p53 interaction can serve as an excellent example of the complexity of p53 signaling pathways."
24180275
sparser
"We identified an optimal peptide named MIP that inhibited the MDM2-p53 and MDMX-p53 interactions 29- and 13-fold more effectively than DI, respectively."
21423613
sparser
"Specifically, we show that the binding of the p53 tumor suppressor to its two major negative regulators, MDM2 and MDM4, can be simultaneously measured within the same sample, without the requirement for complex filters or deconvolution."
26646257
sparser
"In addition, when Mdm2 and/or Mdm4 are bound to p53, they mask the transactivation domain."
27252909
sparser
"Mdm2 and Mdmx bind to the amino terminal transactivation domain of p53 to block transcriptional activity [ xref , xref , xref , xref ]."
20651945
sparser
"In an unstressed environment, however, p53 is prevented from transactivating target genes by its interaction with MDM2 and the closely-related MDM4 proteins. xref Both MDM2 and MDM4 can bind independently to p53 through their N-termini, but can also bind to each other to form heterodimers through the C-terminal RING domain."
26876197
sparser
"The p53:Mdm2 and p53:Mdm4 interactions are an example of a relatively small group of interactions that have been successfully targeted successfully using both classical small molecule approaches and methodologies utilizing new modalities (e.g. stapled peptides)."
31784573
sparser
"P53 interacts with the N-terminal domains of MDM2 and MDMX via its N-terminal TAD."
30726928
sparser
"In attempts to gain a better understanding of the interactions between Mdm2, Mdm4, and p53, multiple mouse models were created that alter the intrinsic functions of Mdm2 or Mdm4 in order to examine their physiological importance."
28093454
sparser
"We therefore decided to develop the Flu orescent PPI -visualization (FLUOPPI xref ) to enable the simultaneous measurement of both Mdm2:p53 and Mdm4:p53 interactions in order to assess the relative efficiencies of mimetic molecules of the p53 peptide helix against both PPIs."
31784573
sparser
"Development of inhibitors to disrupt the interactions of p53 with either Mdm2 or Mdm4, or both, are therefore highly desirable as they will prevent p53 degradation and restore a p53 dependent transcriptional anti-tumour response xref ."
31784573
sparser
"MDM2 and its homolog MDMX bind to the tumor suppressor p53 and regulate its stability and activity."
21171592
sparser
"The structural basis for the interaction of p53 with the N-terminal domains of MDM2 and MDMX is well understood. xref ; xref ; xref The N-terminal transactivation domain of p53 is disordered in solution, xref ; xref ; xref and becomes partially structured upon MDM2 or MDMX binding."
20226197