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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 6

PMID 24900694

Citations 154

Authors

Binh Vu

Peter Wovkulich

Giacomo Pizzolato

Allen Lovey

Qingjie Ding

Nan Jiang

Jin-Jun Liu

Chunlin Zhao

Kelli Glenn

Yang Wen

Christian Tovar

Kathryn Packman

Lyubomir Vassilev

Bradford Graves

Affiliations

Soon will be listed here.

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.

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References

Kussie P, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine A . Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996; 274(5289):948-53. DOI: 10.1126/science.274.5289.948. View

Vassilev L . MDM2 inhibitors for cancer therapy. Trends Mol Med. 2006; 13(1):23-31. DOI: 10.1016/j.molmed.2006.11.002. View

Harris S, Levine A . The p53 pathway: positive and negative feedback loops. Oncogene. 2005; 24(17):2899-908. DOI: 10.1038/sj.onc.1208615. View

Vu B, Vassilev L . Small-molecule inhibitors of the p53-MDM2 interaction. Curr Top Microbiol Immunol. 2010; 348:151-72. DOI: 10.1007/82_2010_110. View

Hainaut P, Hollstein M . p53 and human cancer: the first ten thousand mutations. Adv Cancer Res. 1999; 77:81-137. DOI: 10.1016/s0065-230x(08)60785-x. View

FREEDMAN D, Wu L, Levine A . Functions of the MDM2 oncoprotein. Cell Mol Life Sci. 1999; 55(1):96-107. PMC: 11146946. DOI: 10.1007/s000180050273. View

Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M . MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 2013; 73(8):2587-97. DOI: 10.1158/0008-5472.CAN-12-2807. View

Kubbutat M, Jones S, Vousden K . Regulation of p53 stability by Mdm2. Nature. 1997; 387(6630):299-303. DOI: 10.1038/387299a0. View

Ashcroft M, Vousden K . Regulation of p53 stability. Oncogene. 2000; 18(53):7637-43. DOI: 10.1038/sj.onc.1203012. View

10.

Vogelstein B, Lane D, Levine A . Surfing the p53 network. Nature. 2000; 408(6810):307-10. DOI: 10.1038/35042675. View

11.

Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H . Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A. 2006; 103(6):1888-93. PMC: 1413632. DOI: 10.1073/pnas.0507493103. View

12.

Levine A . p53, the cellular gatekeeper for growth and division. Cell. 1997; 88(3):323-31. DOI: 10.1016/s0092-8674(00)81871-1. View

13.

Ray-Coquard I, Blay J, Italiano A, Cesne A, Penel N, Zhi J . Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012; 13(11):1133-40. DOI: 10.1016/S1470-2045(12)70474-6. View

14.

Brown C, Lain S, Verma C, Fersht A, Lane D . Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009; 9(12):862-73. DOI: 10.1038/nrc2763. View

15.

Bond G, Hu W, Levine A . MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets. 2005; 5(1):3-8. DOI: 10.2174/1568009053332627. View

16.

Vassilev L, Vu B, Graves B, Carvajal D, Podlaski F, Filipovic Z . In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004; 303(5659):844-8. DOI: 10.1126/science.1092472. View

17.

Momand J, Zambetti G, Olson D, George D, Levine A . The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992; 69(7):1237-45. DOI: 10.1016/0092-8674(92)90644-r. View

18.

Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S . Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem. 2006; 49(12):3432-5. DOI: 10.1021/jm051122a. View

19.

Iwakuma T, Lozano G . MDM2, an introduction. Mol Cancer Res. 2004; 1(14):993-1000. View

20.

Rew Y, Sun D, Gonzalez-Lopez de Turiso F, Bartberger M, Beck H, Canon J . Structure-based design of novel inhibitors of the MDM2-p53 interaction. J Med Chem. 2012; 55(11):4936-54. DOI: 10.1021/jm300354j. View