Identification and Characterization of the First Small Molecule Inhibitor of MDMX
Open accessAbstract
The p53 pathway is disrupted in virtually every human tumor. In approximately 50% of human cancers, the p53 gene is mutated, and in the remaining cancers, the pathway is dysregulated by genetic lesions in other genes that modulate the p53 pathway. One common mechanism for inactivation of the p53 pathway in tumors that express wild-type p53 is increased expression of MDM2 or MDMX. MDM2 and MDMX bind p53 and inhibit its function by distinct nonredundant mechanisms. Small molecule inhibitors and small peptides have been developed that bind MDM2 in the p53-binding pocket and displace the p53 protein, leading to p53-mediated cell cycle exit and apoptosis. To date, peptide inhibitors of MDMX have been developed, but no small molecule inhibitors have been reported. We have developed biochemical and cell-based assays for high throughput screening of chemical libraries to identify MDMX inhibitors and identified the first MDMX inhibitor SJ-172550. This compound binds reversibly to MDMX and effectively kills retinoblastoma cells in which the expression of MDMX is amplified. The effect of SJ-172550 is additive when combined with an MDM2 inhibitor. Results from a series of biochemical and structural modeling studies suggest that SJ-172550 binds the p53-binding pocket of MDMX, thereby displacing p53. This lead compound is a useful chemical scaffold for further optimization of MDMX inhibitors that may eventually be used to treat pediatric cancers and various adult tumors that overexpress MDMX or have similar genetic lesions. When combined with selective MDM2 inhibitors, SJ-172550 may also be useful for treating tumors that express wild-type p53.
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The small molecule SJ-172550 was identified as an MDMX-p53-selective antagonist, but subsequent analyses showed that it forms covalent adducts with cysteine residues in the p53-binding domain of both MDM2 and MDMX.
“The small molecule SJ-172550 was identified as an MDMX–p53-selective antagonist105 that exhibited additive cytotoxicity with nutlin 3a in MDMX-amplified retinoblastoma cells. However, subsequent analyses showed that SJ-172550 forms covalent adducts with cysteine residues in the p53-binding domain of both MDM2 and MDMX.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [105]
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“SJ-172550 MDM4 Small molecule [73] XI-006 MDM4 Small molecule [74]”
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“Mdm2 is an E3 ubiquitin ligase that targets p53 target genes Mdm2 Mdm4 p53 p53 p53 p53* Rx Rx PRIMA-1MET CP31398 PhiKan083 MIRA-3 STIMA-1 SCH529074 Ellipticine RETRA p53R3 WR1065 Nutlins Sulfonamide I NSC66811 Terphenyl 14 TDP665759 TDP521252 MI-219/-319 PXn727/822 Isoindolinone 74a SJ-172550 XI-006 RITA JNJ-26854165…”
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“Moreover, a synthesized antagonist, SJ172550, of the MDM4-p53 interaction effectively kills retinoblastoma cells with elevated MDM4 and has additive effects with nutlin-3 [160].”
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Herman, A. G., Hayano, M., Poyurovsky, M. V., Shimada, K., Skouta, R., Prives, C., & Stockwell, B. R. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0104 · Cited by 100 · see citing works
“More recently, the first small-molecule inhibitor of MdmX binding to p53 was identified (39).”
Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives
Fang, Y., Liao, G., & Yu, B. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.01.003 · Cited by 106 · see citing works
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Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics
Zhao, Y., Bernard, D., & Wang, S. (2013) · Biodiscovery · doi:10.7750/biodiscovery.2013.8.4 · Cited by 89 · see citing works
“For example, Reed and co-workers used high-throughput screening to assess a library of 295,848 unique compounds using an in vitro fluorescence polarization binding assay [77].”
BackgroundMethodPAINS: Relevance to Tool Compound Discovery and Fragment-Based Screening
Baell, J. B., Ferrins, L., Falk, H., & Nikolakopoulos, G. (2013) · Australian Journal of Chemistry · doi:10.1071/ch13551 · Cited by 87 · see citing works
Trophoblast Induces Monocyte Differentiation Into CD 14+/ CD 16+ Macrophages
Aldo, P. B., Racicot, K. E., Craviero, V., Guller, S. M., Romero, R. J., & Mor, G. (2014) · American Journal of Reproductive Immunology · doi:10.1111/aji.12288 · Cited by 86 · see citing works
Towards an understanding of the role of p53 in adrenocortical carcinogenesis
Wasserman, J. D., Zambetti, G. P., & Malkin, D. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.09.010 · Cited by 84 · see citing works
“Indeed a small-molecule inhibitor of MDMX was recently described (Popowicz et al., 2010; Reed et al., 2010).”
Validation of MdmX as a therapeutic target for reactivating p53 in tumors
Garcia, D., Warr, M. R., Martins, C. P., Brown Swigart, L., Passegué, E., & Evan, G. I. (2011) · Genes & Development · doi:10.1101/gad.16722111 · Cited by 83 · see citing works
“The recent identification of the first small-molecule inhibitor of MdmX (Reed et al. 2010) may therefore be an important step forward in the genesis of novel therapies that are truly tumor-specific.”
BackgroundLi, Y., Rodewald, L. W., Hoppmann, C., Wong, E. T., Lebreton, S., Šafář, P., Pátek, M., Wang, L., Wertman, K. F., & Wahl, G. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.058 · Cited by 83 · see citing works
“In contrast, other published antagonists (SJ-172550 and RO-5963) showed little if any PPI disruption activity in cells.”
BackgroundMethodTargeting p53-MDM2-MDMX Loop for Cancer Therapy
Zhang, Q., Zeng, S. X., & Lu, H. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_16 · Cited by 83 · see citing works
“SJ172550 interferes with the MDMX-p53 interaction [58, 59], while XI-006 inhibits MDMX transcription [60].”
BackgroundMedicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction
Lemos, A., Leão, M., Soares, J., Palmeira, A., Pinto, M. M. M., Saraiva, L., & Sousa, M. E. (2016) · Medicinal Research Reviews · doi:10.1002/med.21393 · Cited by 83 · see citing works
MDMX (MDM4), a Promising Target for p53 Reactivation Therapy and BeyondPreprint
Marine, J., & Jochemsen, A. G. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026237 · Cited by 81 · see citing works
“A specific inhibitor of the MDMX–p53 interaction has been reported, but the very complex mechanism of action prevents the further development into a clinically relevant compound (Reed et al. 2010; Bista et al. 2012).”
BackgroundSelf-citationReviving the guardian of the genome: Small molecule activators of p53
Nguyen, D., Liao, W., Zeng, S. X., & Lu, H. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.03.013 · Cited by 80 · see citing works
“…2012; Yang et al., 2005) SP-141 Pyirdo[b]indole MDM2 degradation (Wang et al., 2014) SJ-172550 imidazoline MDMX:p53 antagonist (Bista et al., 2012; Reed et al., 2010) XI-006 (NSC207895) Benzofuroxan MDMX:p53 antagonist (Pishas et al., 2015; H. Wang et al., 2011) XI-011 (NSC146109) Pseudourea…”
BackgroundTranslational approaches targeting the p53 pathway for anti‐cancer therapy
Essmann, F., & Schulze‐Osthoff, K. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01570.x · Cited by 77 · see citing works
“Interestingly, high-throughput screening of drug libraries recently identified SJ-172550 (CAS 431979-47-4) as a lead compound that interferes with p53:MDMX interaction and showed p53-dependent cytotoxic effects in tumour cell lines (Reed et al., 2010).”
BackgroundPharmacological reactivation of p53 as a strategy to treat cancer
Zawacka‐Pankau, J., & Selivanova, G. (2015) · Journal of Internal Medicine · doi:10.1111/joim.12336 · Cited by 82 · see citing works
Pecháčková, S., Burdová, K., Benada, J., Kleiblová, P., Jeníková, G., & Macůrek, L. (2016) · Oncotarget · doi:10.18632/oncotarget.7363 · Cited by 75 · see citing works
Schedule-dependent interaction between anticancer treatments
Chen, S., Forrester, W. C., & Lahav, G. (2016) · Science · doi:10.1126/science.aac5610 · Cited by 73 · see citing works
Targeting Mutant p53 in Human Tumors
Lehmann, B. D., & Pietenpol, J. A. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.0412 · Cited by 72 · see citing works
Nutlin-3a Is a Potential Therapeutic for Ewing Sarcoma
Pishas, K. I., Al-Ejeh, F., Zinonos, I., Kumar, R., Evdokiou, A., Brown, M. P., Callen, D. F., & Neilsen, P. M. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1587 · Cited by 71 · see citing works
“MDM4 inhibition was achieved using a recently identified specific MDM4 antagonist, SJ-172550 (34).”
MethodInfluentialAdvanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer
Zhang, S., Carlsen, L., Borrero, L. J. H., Seyhan, A. A., Tian, X., & El‐Deiry, W. S. (2022) · Biomolecules · doi:10.3390/biom12040548 · Cited by 71 · see citing works
“Treatment with SJ-172550 combined with MDM2 inhibitors additively suppresses tumor growth [95].”
BackgroundThe long and the short of it: the MDM4 tail so far
Haupt, S., Mejía-Hernández, J. O., Vijayakumaran, R., Keam, S. P., & Haupt, Y. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz007 · Cited by 69 · see citing works
“, 2016) and high CK1α activity would be anticipated to be oncogenic, which is in keeping with recent findings demonstrating CK1α overexpression correlates with poor survival in colorectal cancer (Richter et al., 2018).”
BackgroundResultSynthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents
Ribeiro, C. J. A., Amaral, J. D., Rodrigues, C. M. P., Moreira, R., & Santos, M. M. M. (2013) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.10.048 · Cited by 67 · see citing works
Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis
Carr, M. I., & Jones, S. N. (2016) · Translational Cancer Research · doi:10.21037/tcr.2016.11.75 · Cited by 70 · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (WK 298 and SJ-172550) (238,239), as well as molecules that inhibit MdmX transcription (NSC 207895) (240) or stability (17-AAG) (241).”
BackgroundMaslon, M. M., & Hupp, T. R. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.06.005 · Cited by 66 · see citing works
It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy
Kung, C.-P., & Weber, J. D. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.818744 · Cited by 68 · see citing works
Wild type p53 reactivation: From lab bench to clinic
Selivanova, G. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.03.049 · Cited by 65 · see citing works
“has been discovered using high throughput biochemical screen [43].”
MethodJoshi, Y., Sória, M. G., Quadrato, G., Inak, G., Zhou, L., Hervera, A., Rathore, K. I., Elnaggar, M., Cucchiarini, M., Marine, J., et al. (2015) · Brain · doi:10.1093/brain/awv125 · Cited by 65 · see citing works
“The recent discovery of specific small molecule inhibitors of MDM4 (Reed et al., 2010; Vogel et al., 2012), which are still awaiting confirmation in multiple studies, may also expand our regenerative therapeutic options.”
BackgroundNutlin-3, A p53-Mdm2 Antagonist for Nasopharyngeal Carcinoma Treatment
VOON, Y.-L., Wong, P., & Khoo, A. S. B. (2017) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557517666170717125821 · Cited by 65 · see citing works
Small molecule compounds targeting the p53 pathway: are we finally making progress?
Yu, X., Narayanan, S., Vázquez, A., & Carpizo, D. R. (2014) · APOPTOSIS · doi:10.1007/s10495-014-0990-3 · Cited by 65 · see citing works
“Table 1 Compounds and small molecules that target wild-type and mutant p53 Molecule/compound Mechanism of action Target Stage of development Activate wild-type p53 Nutlins RG7112 (RO5045337) Inhibits p53-MDM2 binding MDM2 Phase I clinical trial (NCT01164033, NCT01143740, NCT00623870 and NCT00559533) [48] Benzodiazepin…”
Preparation of (−)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale
Davis, T. A., Vilgelm, A. E., Richmond, A. J., & Johnston, J. N. (2013) · The Journal of Organic Chemistry · doi:10.1021/jo401321a · Cited by 62 · see citing works
Computational approaches for the design of modulators targeting protein-protein interactions
Rehman, A. U., Khurshid, B., Ali, Y., Rasheed, S., Wadood, A., Ng, H. L., Chen, H., Wei, Z., Luo, R., & Zhang, J. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2171396 · Cited by 62 · see citing works
“Small molecule MDMX inhibitors have also failed to work in cultured cells [145].”
BackgroundWhen the guardian sleeps: Reactivation of the p53 pathway in cancer
Merkel, O., Taylor, N., Prutsch, N., Staber, P. B., Moriggl, R., Turner, S. D., & Kenner, L. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.02.003 · Cited by 54 · see citing works
“One of the first of this class of compounds is SJ-172550, which binds reversibly to MDMX inhibiting the p53 binding domain and inducing apoptosis in retinoblastoma cells known to express high levels of MDMX (Reed et al., 2010).”
BackgroundTargeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
DeVine, T., & Dai, M. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319180009 · Cited by 57 · see citing works
On the Mechanism of Action of SJ-172550 in Inhibiting the Interaction of MDM4 and p53
Bista, M., Smithson, D., Pecak, A., Salinas, G., Pustelny, K., Min, J., Pirog, A., Finch, K., Zdzalik, M., Waddell, B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037518 · Cited by 58 · see citing works
“The first (Figure 1, Panel A, SJ-172550, 1) was identified in a high-throughput screen using a biochemical assay to recapitulate the binding of MDMX and p53 [10].”
BackgroundMethodResultInfluentialSelf-citationVaseva, A. V., Yallowitz, A. R., Marchenko, N. D., Xu, S., & Moll, U. M. (2011) · Cell Death & Disease · doi:10.1038/cddis.2011.39 · Cited by 55 · see citing works
Extended String Binding Mode of the Phosphorylated Transactivation Domain of Tumor Suppressor p53
Okuda, M., & Nishimura, Y. (2014) · Journal of the American Chemical Society · doi:10.1021/ja506351f · Cited by 52 · see citing works
Wardelmann, E., Schildhaus, H., Merkelbach‐Bruse, S., Hartmann, W., Reichardt, P., Hohenberger, P., & Büttner, R. (2010) · Annals of Oncology · doi:10.1093/annonc/mdq381 · Cited by 52 · see citing works
“From the translational point of view, linking genetics and treatment, MDM2 could be a promising therapeutic target [26, 27].”
Ubiquitylation of p53 by the APC/C inhibitor Trim39
Zhang, L., Huang, N.-J., Chen, C., Tang, W., & Kornbluth, S. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1212047110 · Cited by 51 · see citing works
“For example, nutlin-3a is already known to be ineffective in cells that express high levels of MDMX, another known p53-directed ligase (28–30).”
BackgroundInfluentialVara, B., Mayasundari, A., Tellis, J. C., Danneman, M. W., Arredondo, V., Davis, T. A., Min, J., Finch, K. E., Guy, R. K., & Johnston, J. N. (2014) · The Journal of Organic Chemistry · doi:10.1021/jo501003r · Cited by 50 · see citing works
Self-citationTargeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges
Yu, D.-H., Xu, Z., Mo, S., Li, Y., Cheng, X., & Qin, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01389 · Cited by 51 · see citing works
“Jude chemical library (containing 295,848 unique compounds) by using a fluorescence polarization (FP)-based MDMX-p53 binding assay as well as a cell-based assay and identified 11 representative compounds (94).”
BackgroundMethodInfluentialWang, H., & Yan, C. (2011) · Neoplasia · doi:10.1593/neo.11438 · Cited by 49 · see citing works
“Previously, only two small molecules have been found to targetMDMX, that is, SJ-172250, a compound that binds MDMX and blocks the p53-MDMX interaction [24], and XI-006, a benzofuroxan derivative that inhibits MDMX expression [27].”
BackgroundTP53-Associated Pediatric Malignancies
Pinto, E. M., Ribeiro, R. C., de Figueiredo, B. C., & Zambetti, G. P. (2011) · Genes & Cancer · doi:10.1177/1947601911409745 · Cited by 49 · see citing works
“20,21 The importance of this interaction in regulating p53-dependent tumor suppression is highlighted by the following findings: 1) Studies in animal models have shown that the embryonic lethality of Mdm2 knockout mice can be fully rescued by deleting p53, 2) Mdm2 transgenic mice are tumor prone, 3) MDM2 is frequently…”
BackgroundAn Update on MDMX and Dual MDM2/X Inhibitors
Espadinha, M., Barcherini, V., Lopes, E. A., & Santos, M. M. M. (2018) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026618666180604080119 · Cited by 49 · see citing works
Zhang, S., Lou, J., Li, Y., Zhou, F., Yan, Z., Lyu, X., & Zhao, Y. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00940 · Cited by 47 · see citing works
Soares, J., Espadinha, M., Raimundo, L., Ramos, H., Gomes, A. S., Gomes, S., Loureiro, J. B., Inga, A., Reis, F., Gomes, C. M. F., et al. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12051 · Cited by 46 · see citing works
“Nutlin-3a and SJ-172550 were used as positive controls because, as in human cells (Reed et al., 2010; Vassilev et al., 2004), they inhibit the negative effect of MDM2 and MDMX, respectively, having no impact on the other MDM (Fig.”
BackgroundDruggability Assessment of Protein–Protein Interfaces
Wanner, J., Fry, D. C., Peng, Z., & Roberts, J. (2011) · Future Medicinal Chemistry · doi:10.4155/fmc.11.156 · Cited by 44 · see citing works
Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering
Pérez, J. J., Pérez, R. A., & Pérez, A. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.681617 · Cited by 43 · see citing works
“Furthermore, small molecules inhibitors of MDMX have not been successful in culture cells (Reed et al., 2010).”
BackgroundSpinnler, C., Hedström, E., Li, H., de Lange, J., Nikulenkov, F., Teunisse, A. F. A. S., Vries, M. V., Grinkevich, V. V., Jochemsen, A. G., & Selivanova, G. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.45 · Cited by 42 · see citing works
“Recently, the chemical inhibitor of HdmX/p53 interaction, SJ-172550 has been found, which displays additive effects in cancer cells when combined with an Hdm2 inhibitor.(19) Wild-type p53-induced phosphatase 1 (Wip1), encoded by the PPM1D gene, is a serine/threonine phosphatase that”
BackgroundSelf-citationSynthesis and cytotoxic properties of novel (E)-3-benzylidene-7-methoxychroman-4-one derivatives
Noushini, S., Alipour, E., Emami, S., Safavi, M., Ardestani, S. K., Gohari, A. R., Shafiee, A., & Foroumadi, A. (2013) · DARU Journal of Pharmaceutical Sciences · doi:10.1186/2008-2231-21-31 · Cited by 40 · see citing works
“Recently, high-throughput screening of drug libraries results in the identification of SJ-172550 that exhibited p53-dependent cytotoxic activity against cancer cell lines [11].”
BackgroundThe Pharmacodynamics of the p53-Mdm2 Targeting Drug Nutlin: The Role of Gene-Switching Noise
Puszyński, K., Gandolfi, A., & d’Onofrio, A. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003991 · Cited by 39 · see citing works
“Anyway, including MDMX among the players of the model would increase its flexibility, also allowing for the quantification of the action of MDMX-targeting drugs [77,78].”
BackgroundPharmacological Activation of p53 in Cancer Cells
Athar, M., Elmets, C. A., & Kopelovich, L. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795222595 · Cited by 38 · see citing works
Chemical Variations on the p53 Reactivation Theme
Ribeiro, C. J. A., Rodrigues, C. M. P., Moreira, R., & Santos, M. M. M. (2016) · Pharmaceuticals · doi:10.3390/ph9020025 · Cited by 35 · see citing works
“This compound was found to bind reversibly to MDMX in the p53 binding pocket, and showed cytotoxicity in MDMX-amplified retinoblastoma cell line Weri1 [149].”
BackgroundSmall Molecule Modulators of RING-Type E3 Ligases: MDM and Cullin Families as Targets
Bulatov, E., Zagidullin, A. A., Valiullina, A., Sayarova, R., & Rizvanov, A. A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00450 · Cited by 33 · see citing works
“To date a certain progress was achieved in development of p53/MDM4 inhibitors such as SJ-172550 (Reed et al., 2010; Bista et al., 2012), WK298 (Popowicz et al., 2010) and stabilized peptide SAH-p53-c8 (Bernal et al., 2010).”
Backgroundp73: From the p53 shadow to a major pharmacological target in anticancer therapy
Ramos, H., Raimundo, L., & Saraiva, L. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105245 · Cited by 31 · see citing works
Stochastic and Deterministic Models of Cellular p53 Regulation
Leenders, G. B., & Tuszyński, J. A. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00064 · Cited by 28 · see citing works
“Small molecule inhibitors of MDMX have only recently been discovered (Reed et al., 2010).”
BackgroundNovel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis
Fedorova, O., Daks, A. A., Petrova, V., Petukhov, A., Lezina, L., Shuvalov, O. Y., Davidovich, P. B., Kriger, D. V., Lomert, E. V., Tentler, D., et al. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1506664 · Cited by 30 · see citing works
“To this end, a number of small molecules and stapled peptides targeting the p53-Mdm2 interaction (such as Nutlins (Nutlin-3a, RG7112, RG7388) [31–33], SJ-172,550 [34], ATSP-7041 [35]) have been developed and are currently in different phases of clinical trials.”
BackgroundInauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth
Zhang, Y.-W., Zhang, Q., Zeng, S. X., Zhang, Y., Mayo, L. D., & Lu, H. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.20844 · Cited by 28 · see citing works
Dey, A., Lane, D. P., & Verma, C. S. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.02.004 · Cited by 27 · see citing works
Improving anticancer activity towards colon cancer cells with a new p53‐activating agent
Raimundo, L., Espadinha, M., Soares, J., Loureiro, J. B., Alves, M. G., Santos, M. M. M., & Saraiva, L. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14468 · Cited by 28 · see citing works
“, 2004) or MDMX (such as SJ-172550; Reed et al., 2010) abolish the MDM2 or MDMX inhibitory effect, respectively, with the re-establishment of the p53-induced growth arrest.”
BackgroundRecent Synthetic Approaches towards Small Molecule Reactivators of p53
Silva, J. L., Lima, C. G. S., Rangel, L. P., Ferretti, G. D. S., Pauli, F. P., Ribeiro, R. C. B., Silva, T. B., da Silva, F. D. C., & Ferreira, V. F. (2020) · Biomolecules · doi:10.3390/biom10040635 · Cited by 28 · see citing works
“The base- catalyzed reaction of 189 with fragment 187 gives rise to the product SJ-172550.”
BackgroundInfluentialBlackburn, T. J., Ahmed, S. U., Coxon, C. R., Liu, J., Lü, X., Golding, B. T., Griffin, R. J., Hutton, C., Newell, D. R., Ojo, O. S., et al. (2013) · MedChemComm · doi:10.1039/c3md00161j · Cited by 27 · see citing works
Merlino, F., Daniele, S., Pietra, V. L., Maro, S. D., Leva, F. S. D., Brancaccio, D., Tomassi, S., Giuntini, S., Cerofolini, L., Fragai, M., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00004 · Cited by 27 · see citing works
The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target
Fierabracci, A., & Pellegrino, M. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17121975 · Cited by 26 · see citing works
Calculation of hot spots for protein–protein interaction in p53/PMI‐MDM2/MDMX complexes
Huang, D., Qi, Y., Song, J., & Zhang, J. Z. H. (2018) · Journal of Computational Chemistry · doi:10.1002/jcc.25592 · Cited by 26 · see citing works
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“Furthermore, this result has been supported by the studies of several other groups [16,26–32].”
- Authors
- Reed, D., Shen, Y., Shelat, A. A., Arnold, L. A., Ferreira, A. M., Zhu, F., Mills, N., Smithson, D. C., Regni, C. A., Bashford, D., Cicero, S. A., Schulman, B. A., Jochemsen, A. G., Guy, R. K., & Dyer, M. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Leiden University Medical Center (NL)
- Corresponding author
- Dyer, Michael A.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 285
- Issue
- 14
- Pages
- 10786-10796
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2856285
- OpenAlex
- W1997557358
- Cited by
- 198
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 10 · 2018: 10 · 2017: 14 · 2016: 19 · 2015: 9 · 2014: 25 · 2013: 20 · 2012: 15
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- International Retinal Research Foundation
- Research to Prevent Blindness
- Vanderbilt University
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Eye Institute (R01EY014867)
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDMX, small molecule inhibitors, p53 pathway, MDM2, retinoblastoma, MDM2 inhibitors, combination therapy, high-throughput screening, childhood cancer
- MeSH terms
- Acetates, Animals, Antineoplastic Agents, Computer Simulation, Humans, Pyrazoles, Retinoblastoma, Tumor Suppressor Protein p53, Apoptosis, Cell Line, Tumor, Mice, Proto-Oncogene Proteins c-mdm2, Small Molecule Libraries, High-Throughput Screening Assays
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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