SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression

Cancer Research

Volumn 74, Issue 20, 2014, Pages 5855-5865

  Wang, Shaomeng ^a,b,c   Sun, Wei ^a,b   Zhao, Yujun ^a,b   McEachern, Donna ^a,b   Meaux, Isabelle ^d   Barrière, Cédric ^d   Stuckey, Jeanne A ^c   Meagher, Jennifer L ^c   Bai, Longchuan ^a,b   Liu, Liu ^a,b   Hoffman Luca, Cassandra Gianna ^a,b   Lu, Jianfeng ^a,b   Shangary, Sanjeev ^a,b   Yu, Shanghai ^a,b   Bernard, Denzil ^a,b   Aguilar, Angelo ^a,b   Dos Santos, Odette ^d   Besret, Laurent ^d   Guerif, Stéhane ^d   Pannier, Pascal ^d   Gorge Bernat, Dimitri ^d   Debussche, Laurent ^d   more..

^a UNIVERSITY OF MICHIGAN COMPREHENSIVE CANCER CENTER   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF MICHIGAN   (United States)

^d SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; PROTEIN MDM2; PROTEIN P53; SAR 405838; UNCLASSIFIED DRUG; APOPTOSIS REGULATORY PROTEIN; BBC3 PROTEIN, HUMAN; INDOLE DERIVATIVE; MDM2 PROTEIN, HUMAN; ONCOPROTEIN; PROTEIN BINDING; SAR405838; SPIRO COMPOUND; TP53 PROTEIN, HUMAN;

ACUTE LEUKEMIA; AMINO TERMINAL SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; BINDING AFFINITY; CANCER INHIBITION; CELL CYCLE ARREST; COLON CANCER; COMPLEX FORMATION; CONTROLLED STUDY; DOSE RESPONSE; DRUG BINDING; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENCY; DRUG SPECIFICITY; DRUG STABILITY; DRUG STRUCTURE; DRUG TOLERABILITY; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LEUKEMIA; MALE; MOUSE; NONHUMAN; OSTEOSARCOMA; PROSTATE CANCER; PROTEIN PROTEIN INTERACTION; SINGLE DRUG DOSE; SOLID TUMOR; TUMOR XENOGRAFT; UPREGULATION; ANIMAL; CELL CYCLE CHECKPOINT; CELL PROLIFERATION; DOG; DRUG EFFECTS; DRUG SCREENING; HCT116 CELL LINE; METABOLISM; RAT; REMISSION;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; CELL CYCLE CHECKPOINTS; CELL PROLIFERATION; DOGS; DRUG STABILITY; HCT116 CELLS; HUMANS; INDOLES; MICE; PROTEIN BINDING; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-MDM2; RATS; REMISSION INDUCTION; SPIRO COMPOUNDS; TUMOR SUPPRESSOR PROTEIN P53; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84908148515     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-14-0799     Document Type: Article

References (41)

1. Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 2000;77:81-137.
2. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm2 autoregulatory feedback loop. Genes Dev 1993;7:1126-32.
3. Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein. Cell Mol Life Sci 1999;55:96-107.
4. Momand J, Wu HH, Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein. Gene 2000;242:15-29.
5. Bond GL, Hu W, Levine AJ. MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 2005;5:3-8.
6. Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res 1998;26:3453-9.
7. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004;303:844-8.
8. Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci U S A 2008;105:3933-8.
9. Vassilev LT. p53 Activation by small molecules: application in oncology. J Med Chem 2005;48:4491-9.
10. Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med 2007;13:23-31.
11. Shangary S, Wang S. Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res 2008;14:5318-24.
12. Wang S, Zhao Y, Bernard D, Aguilar A, Kumar S. Targeting the MDM2-p53 protein-protein interaction for new cancer therapeutics. Top Med Chem 2012;8:57-80.
13. Carry JC, Garcia-Echeverria C. Inhibitors of the p53/hdm2 protein-protein interaction-Path to the clinic. Bioorg Med Chem Letters 2013;23:2480-5.
14. Zhao Y, Bernard D, Wang S. Small molecule inhibitors of MDM2-p53 and MDMX-p53 interaction as new cancer therapeutics. BioDiscovery 2013;8.
15. Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, et al. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J Med Chem 2013;56:5553-61.
16. Zhou H, Chen J, Meagher JL, Yang CY, Aguilar A, Liu L, et al. Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold. J Med Chem 2012;55:4664-82.
17. Kawamoto SA, Thompson AD, Coleska A, Nikolovska-Coleska Z, Yi H, Wang S. Analysis of the interaction of BCL9 with beta-catenin and development of fluorescence polarization and surface plasmon resonance binding assays for this interaction. Biochemistry 2009;48:9534-41.
18. Concepcion J, Witte K, Wartchow C, Choo S, Yao D, Persson H, et al. Label-free detection of biomolecular interactions using BioLayer interferometry for kinetic characterization. Comb Chem High Throughput Screen 2009;12:791-800.
19. Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D. Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 2002;295:868-72.
20. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ. Phaser crystallographic software. J Appl Crystallogr 2007;40:658-67.
21. Emsley P, Cowtan K. Coot: model-building tools for molecular graphics. Acta Crystallographica Section D Biolo Crystallogr 2004;60:2126-32.
22. Bricogne G, Blanc E, Brandl M, Flensburg C, Keller P, Paciorek W, et al. BUSTER. Cambridge, United Kingdom: Global Phasing Ltd; 2011.
23. Teodoro JG, Evans SK, Green MR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med 2007;85:1175-86.
24. Verhaegen M, Bauer JA, Martín de la Vega C, Wang G, Wolter KG, Brenner JC, et al. A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species. Cancer Res 2006;66:11348-59.
25. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677-81.
26. Friberg A, Vigil D, Zhao B, Daniels RN, Burke JP, Garcia-Barrantes PM, et al. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J Med Chem 2013;56:15-30.
27. Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu WQ. Crystal structure of a beta-catenin/BCL9/Tcf4 complex. Mol Cell 2006;24:293-300.
28. Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 1996;274:948-53.
29. Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A 2006;103:1888-93.
30. van Delft MF, Huang DCS. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res 2006;16:203-13.
31. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995;80:293-9.
32. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000;288:1053-8.
33. Shibue T, Suzuki S, Okamoto H, Yoshida H, Ohba Y, Takaoka A, et al. Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways. EMBO J 2006;25:4952-62.
34. Rew Y, Sun DQ, De Turiso FGL, Bartberger MD, Beck HP, Canon J, et al. Structure-based design of novel inhibitors of the MDM2-p53 interaction. J Med Chem 2012;55:4936-54.
35. Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 2013;73:2587-97.
36. Zhao Y, Liu L, Sun W, Lu J, McEachern D, Li X, et al. Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors. J Am Chem Soc 2013;135:7223-734.
37. Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006;127:1323-34.
38. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007;445:656-60.
39. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007;445:661-5.
40. Weaver J, Downs-Kelly E, Goldblum JR, Turner S, Kulkarni S, Tubbs RR, et al. Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol 2008;21:943-9.
41. Weaver J, Goldblum JR, Turner S, Tubbs RR, Wang WL, Lazar AJ, et al. Detection of MDM2 gene amplification or protein expression distinguishes sclerosing mesenteritis and retroperitoneal fi brosis from inflammatory well-differentiated liposarcoma. Mod Pathol 2009;22:66-70.