P53 mdm2 inhibitors

Current Pharmaceutical Design

Volumn 18, Issue 30, 2012, Pages 4668-4678

  Khoury, Kareem ^a,b,c   Dömling, Alex ^a,b,c  

^a UNIVERSITY OF PITTSBURGH   (United States)

^b UNIVERSITY OF GRONINGEN   (Netherlands)

^c Department of Computational Biology ^*  (United States)

Author keywords

HDM2; MDM2; P53; Protein protein interactions; Small molecule inhibitors

Indexed keywords

1,4 BENZODIAZEPINE 2,5 DIONE DERIVATIVE; ANTINEOPLASTIC AGENT; MI 219; MI 43; MI 63; NUTLIN 3; PROTEIN INHIBITOR; PROTEIN MDM2; PROTEIN P53; PROTEIN P53 MDM2 INHIBITOR; RG 7112; SPIROOXINDOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; BINDING AFFINITY; CRYSTAL STRUCTURE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DOSE ESCALATION; DRUG POTENCY; DRUG SOLUBILITY; DRUG STABILITY; DRUG SYNTHESIS; HUMAN; HYDROGEN BOND; LEUKEMIA; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; SOLID TUMOR;

BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN INTERACTION MAPPING; PROTO-ONCOGENE PROTEINS C-MDM2; SMALL MOLECULE LIBRARIES; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84866371810     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212802651580     Document Type: Review

References (42)

1. Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature 1979; 278(5701): 261-263.
2. Brown C, Lain S, Verma C, Fersht A, Lane D. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 2009; 9(12): 862-873.
3. Liau LM, Weaver CH. Ted Kennedy's Recent Diagnosis of Glioblastoma Raises Awareness of Brain Cancer 2010.
4. Halatsch ME, Schmidt U, Unterberg A, Vougioukas VI. Uniform MDM2 overexpression in a panel of glioblastoma multiforme cell lines with divergent EGFR and p53 expression status. Anticancer Res 2006; 26(6B): 4191-4194.
5. Wade M, Wahl GM. Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res 2009; 7(1): 1-11.
6. Bernal F, Wade M, Godes M, et al. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 2010; 18(5): 411-422.
7. Khoury K, Popowicz GM, Holak TA, Dömling A. The p53- MDM2/MDMx axis - A chemotype perspective. Med Chem Comm 2011; 2: 246-260.
8. Vousden KH, Lu X. Live or let die: the cell's response to p53. Nat Rev Cancer 2002; 2(8): 594-604.
9. Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992; 356(6366): 215-221.
10. Marine J-CW, Dyer MA, Jochemsen AG. MDMX: From Bench to Bedside. J of Cell Science 2007; 120(3): 371-378.
11. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 2006; 6(12): 909-923.
12. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7(7A): 1126-1132.
13. Momand J, Zambetti G, Olson D, George D, Levine A. The mdm-2oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992; 69(7): 1237-1245.
14. Danovi D, Meulmeester E, Pasini D, et al. Amplification of Mdmx(or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Molecular and cellular biology 2004; 24(13): 5835-5843.
15. Riemenschneider MJ, Buschges R, Wolter M, et al. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res 1999; 59(24): 6091-6096.
16. Clackson T, Wells JA. A hot spot of binding energy in a hormonereceptor interface. Science 1995; 267(5196): 383-386.
17. Kussie PH, Gorina S, Marechal V, et al. Structure of the MDM2Oncoprotein Bound to p53 Tumor Suppressor Transactivation Domain. Science 1996; 274: 948-953.
18. Picksley SM, Vojtesek B, Sparks A, Lane DP. Immunochemical analysis of the interaction of p53 with MDM2; --fine mapping of the MDM2 binding site on p53 using synthetic peptides. Oncogene 1994; 9(9): 2523-2529.
19. Dömling A, Inventor; Selective and Dual-Action p53/MDM2/MDM4 Antagonists patent WO/2008/130614 2008.
20. Klein C, Vassilev LT. Targeting the p53-MDM2 interaction to treatcancer. British journal of cancer 2004; 91: 1415-1419.
21. Fry DC, Emerson SD, Palme S, et al. NMR structure of a complex between MDM2 and a small molecule inhibitor. J Biomol NMR 2004; 30(2): 163-173.
22. Davis TA, Johnston JN. Catalytic, enantioselective synthesis of stilbene cis-diamines: A concise preparation of ()-Nutlin-3, a potent p53/MDM2 inhibitor. Chemical Science 2011; 2: 1076-1079.
23. ClinicalTrials.gov. A Study of RO5045337 [RG7112] in Patients With Advanced Solid Tumors 2010.
24. ClinicalTrials.gov. A Study of RO5045337 [RG7112] in Patients With Hematologic Neoplasms 2010.
25. Andreeff M, Kojima K, Padmanabhan S, et al. Small Molecule May Disarm Enemy of Cancer-Fighting p53. American Society of Hematology Annual Meeting; San Diago, CA2010. p. Abstract #657.
26. Ding K, Lu Y, Nikolovska-Coleska Z, et al. Structure-based design of potent non-peptide MDM2 inhibitors. J Am Chem Soc 2005; 127(29): 10130-10131.
27. Ding K, Wang G, Deschamps JR, Parrish DA, Wang S. Synthesis of spirooxindoles via asymmetric 1,3-dipolar cycloaddition. Tetrahedron Letters 2005; 2005(35): 5949-5951.
28. Shangary S, Ding K, Qiu S, et al. Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer. Mol Cancer Ther 2008; 7(6): 1533-1542.
29. Popowicz GM, Czarna A, Wolf S, et al. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle 2010; 9(6).
30. Shangary S, Qin D, McEachern D, 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(10): 3933-3938.
31. Parks DJ, Lafrance LV, Calvo RR, et al. 1,4-Benzodiazepine-2,5- diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR. Bioorg Med Chem Lett 2005; 15(3): 765-770.
32. Grasberger BL, Lu T, Schubert C, et al. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem 2005; 48(4): 909-912. Epub 2005/02/18.
33. Cummings MD, Schubert C, Parks DJ, et al. Substituted 1,4- benzodiazepine-2,5-diones as alpha-helix mimetic antagonists of the HDM2-p53 protein-protein interaction. Chem Biol Drug Des 2006; 67(3): 201-205.
34. Koblish HK, Zhao S, Franks CF, et al. Benzodiazepinedione inhibitors of the Hdm2: p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 2006; 5(1): 160-169.
35. Marugan JJ, Leonard K, Raboisson P, et al. Enantiomerically pure 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists. Bioorg Med Chem Lett 2008; 16(12): 3115-3120.
36. Parks DJ, LaFrance LV, Calvo RR, et al. Enhanced pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists of the HDM2-p53 protein-protein interaction through structure-based drug design. Bioorg Med Chem Lett 2006; 16(12): 3310-3314.
37. Czarna A, Beck B, Srivastava S, et al. Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists. Angew Chem Int Ed Engl 2010; 49(31): 5352-5356.
38. Huang Y, Wolf S, Bista M, et al. 1,4-Thienodiazepine-2,5-diones via MCR (I): synthesis, virtual space and p53-Mdm2 activity. Chem Biol Drug Des 2010; 76(2): 116-129.
39. Srivastava S, Beck B, Wang W, et al. Rapid and efficienthydrophilicity tuning of p53/mdm2 antagonists. J Comb Chem 2009; 11(4): 631-639.
40. Huang Y, Wolf S, Koes D, et al. Exhaustive Fluorine Scanning toward Potent p53-Mdm2 Antagonists. ChemMedChem 2012; 7(1): 49-52.
41. Bista M, Khoury K, Wolf S, et al. Discovery of an unusual ligandinduced binding pocket in MDM2. PNAS 2012; Submitted
42. Koes D, Khoury K, Huang Y, et al. Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists. PloS one 2012; 7(3): e32839.