4j3e Citations

Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.

ACS Med Chem Lett 4 466-9 (2013)
Related entries: 1rv1, 4ipf

Cited: 55 times
EuropePMC logo PMID: 24900694

Abstract

The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.

Reviews citing this publication (32)

  1. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. Zhao Y, Aguilar A, Bernard D, Wang S. J. Med. Chem. 58 1038-1052 (2015)
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  24. Targeting ubiquitination for cancer therapies. Morrow JK, Lin HK, Sun SC, Zhang S. Future Med Chem 7 2333-2350 (2015)
  25. State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors. Sheng C, Dong G, Miao Z, Zhang W, Wang W. Chem Soc Rev 44 8238-8259 (2015)
  26. Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions. Laraia L, McKenzie G, Spring DR, Venkitaraman AR, Huggins DJ. Chem. Biol. 22 689-703 (2015)
  27. Alternative modulation of protein-protein interactions by small molecules. Fischer G, Rossmann M, Hyvönen M. Curr. Opin. Biotechnol. 35 78-85 (2015)
  28. Small-molecule MDM2-p53 inhibitors: recent advances. Zhang B, Golding BT, Hardcastle IR. Future Med Chem 7 631-645 (2015)
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  31. Targeting apoptosis pathways for new cancer therapeutics. Bai L, Wang S. Annu. Rev. Med. 65 139-155 (2014)
  32. Resistance acquisition to MDM2 inhibitors. Cinatl J, Speidel D, Hardcastle I, Michaelis M. Biochem. Soc. Trans. 42 752-757 (2014)

Articles citing this publication (23)

  1. Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. Andreeff M, Kelly KR, Yee K, Assouline S, Strair R, Popplewell L, Bowen D, Martinelli G, Drummond MW, Vyas P, Kirschbaum M, Iyer SP, Ruvolo V, González GM, Huang X, Chen G, Graves B, Blotner S, Bridge P, Jukofsky L, Middleton S, Reckner M, Rueger R, Zhi J, Nichols G, Kojima K. Clin. Cancer Res. 22 868-876 (2016)
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  3. Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor. Fry DC, Wartchow C, Graves B, Janson C, Lukacs C, Kammlott U, Belunis C, Palme S, Klein C, Vu B. ACS Med Chem Lett 4 660-665 (2013)
  4. Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions†Electronic supplementary information (ESI) available: Experimental details for compound synthesis, analytical data for all compounds and intermediates. Details for the biological evaluation. Further details for the modeling. Table of combustion analysis data. See DOI: 10.1039/c3md00161jClick here for additional data file. Blackburn TJ, Ahmed S, Coxon CR, Liu J, Lu X, Golding BT, Griffin RJ, Hutton C, Newell DR, Ojo S, Watson AF, Zaytzev A, Zhao Y, Lunec J, Hardcastle IR. Medchemcomm 4 1297-1304 (2013)
  5. Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy. Zhang Z, Ding Q, Liu JJ, Zhang J, Jiang N, Chu XJ, Bartkovitz D, Luk KC, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B. Bioorg. Med. Chem. 22 4001-4009 (2014)
  6. Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents. Ribeiro CJ, Amaral JD, Rodrigues CM, Moreira R, Santos MM. Bioorg. Med. Chem. 22 577-584 (2014)
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  8. Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction. Yu M, Wang Y, Zhu J, Bartberger MD, Canon J, Chen A, Chow D, Eksterowicz J, Fox B, Fu J, Gribble M, Huang X, Li Z, Liu JJ, Lo MC, McMinn D, Oliner JD, Osgood T, Rew Y, Saiki AY, Shaffer P, Yan X, Ye Q, Yu D, Zhao X, Zhou J, Olson SH, Medina JC, Sun D. ACS Med Chem Lett 5 894-899 (2014)
  9. Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction. Pan W, Lahue BR, Ma Y, Nair LG, Shipps GW, Wang Y, Doll R, Bogen SL. Bioorg. Med. Chem. Lett. 24 1983-1986 (2014)
  10. Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction. Vaupel A, Bold G, De Pover A, Stachyra-Valat T, Lisztwan JH, Kallen J, Masuya K, Furet P. Bioorg. Med. Chem. Lett. 24 2110-2114 (2014)
  11. Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors. Yu Z, Zhuang C, Wu Y, Guo Z, Li J, Dong G, Yao J, Sheng C, Miao Z, Zhang W. Int J Mol Sci 15 15741-15753 (2014)
  12. Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein-Protein Interaction by a Scaffold-Hopping Approach. Zaytsev A, Dodd B, Magnani M, Ghiron C, Golding BT, Griffin RJ, Liu J, Lu X, Micco I, Newell DR, Padova A, Robertson G, Lunec J, Hardcastle IR. Chem Biol Drug Des 86 180-189 (2015)
  13. Significant Differences in the Development of Acquired Resistance to the MDM2 Inhibitor SAR405838 between In Vitro and In Vivo Drug Treatment. Hoffman-Luca CG, Yang CY, Lu J, Ziazadeh D, McEachern D, Debussche L, Wang S. PLoS ONE 10 e0128807 (2015)
  14. Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells. Sachweh MC, Stafford WC, Drummond CJ, McCarthy AR, Higgins M, Campbell J, Brodin B, Arnér ES, Laín S. Oncotarget 6 16488-16506 (2015)
  15. Structure- and ligand-based virtual screening identifies new scaffolds for inhibitors of the oncoprotein MDM2. Houston DR, Yen LH, Pettit S, Walkinshaw MD. PLoS ONE 10 e0121424 (2015)
  16. Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities. Roth HS, Hergenrother PJ. Curr. Med. Chem. 23 201-241 (2016)
  17. Reactivation of p53 via MDM2 inhibition. Kim ES, Shohet JM. Cell Death Dis 6 e1936 (2015)
  18. Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas. Verreault M, Schmitt C, Goldwirt L, Pelton K, Haidar S, Levasseur C, Guehennec J, Knoff D, Labussière M, Marie Y, Ligon AH, Mokhtari K, Hoang-Xuan K, Sanson M, Alexander BM, Wen PY, Delattre JY, Ligon KL, Idbaih A. Clin. Cancer Res. 22 1185-1196 (2016)
  19. The use of ion mobility mass spectrometry to probe modulation of the structure of p53 and of MDM2 by small molecule inhibitors. Dickinson ER, Jurneczko E, Nicholson J, Hupp TR, Zawacka-Pankau J, Selivanova G, Barran PE. Front Mol Biosci 2 39 (2015)
  20. Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors. Patnaik A, Tolcher A, Beeram M, Nemunaitis J, Weiss GJ, Bhalla K, Agrawal M, Nichols G, Middleton S, Beryozkina A, Sarapa N, Peck R, Zhi J. Cancer Chemother. Pharmacol. 76 587-595 (2015)
  21. Selective and Potent Proteomimetic Inhibitors of Intracellular Protein-Protein Interactions. Barnard A, Long K, Martin HL, Miles JA, Edwards TA, Tomlinson DC, Macdonald A, Wilson AJ. Angew Chem Weinheim Bergstr Ger 127 3003-3008 (2015)
  22. New Approaches to Managing Liposarcoma: Will Cold Steel Remain the Only Way to Heal? Ben Ami E, George S. J Oncol Pract 12 230-231 (2016)
  23. The MDM2 small-molecule inhibitor RG7388 leads to potent tumor inhibition in p53 wild-type neuroblastoma. Lakoma A, Barbieri E, Agarwal S, Jackson J, Chen Z, Kim Y, McVay M, Shohet JM, Kim ES. Cell Death Discov 1 (2015)


Related citations provided by authors (2)

  1. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.. Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT Cancer Res. (2013)
  2. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA Science 303 844-8 (2004)