Small-molecule inhibitors of MDM2 as new anticancer therapeutics

Seminars in Cancer Biology

Volumn 20, Issue 1, 2010, Pages 10-18

  Dickens, Michael P ^a   Fitzgerald, Ross ^a   Fischer, Peter M ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

Benzodiazepinedione; Cancer therapy; Drug discovery and development; E3 ubiquitin ligase inhibitor; MDM2 inhibitor; MDMX; Nongenotoxic p53 activation; Nutlin; Proteasomal degradation; Protein protein interaction; Spiro oxindole

Indexed keywords

5 DEAZAFLAVINE DERIVATIVE; ACRIDINE DERIVATIVE; ANTINEOPLASTIC AGENT; ANTISENSE OLIGONUCLEOTIDE; AT 219; BENZODIAZEPINE DERIVATIVE; ENZYME INHIBITOR; INDOLE DERIVATIVE; JNJ 26854165; MI 219; NUTLIN 3; PROTEIN MDM2; PROTEIN MDM2 INHIBITOR; PROTEIN MDMX; PROTEIN P53; R 7112; SEMPERVIRINE; SULFONAMIDE; TDP 665759; UBIQUITIN PROTEIN LIGASE; UBIQUITIN PROTEIN LIGASE E3 INHIBITOR; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; CANCER CELL; CLINICAL TRIAL; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG STRUCTURE; GENE THERAPY; HEMATOLOGIC MALIGNANCY; HUMAN; NONHUMAN; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW; SOLID TUMOR; TUMOR XENOGRAFT; UBIQUITINATION; WILD TYPE;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; NEOPLASMS; PROTO-ONCOGENE PROTEINS C-MDM2; SMALL MOLECULE LIBRARIES; TUMOR SUPPRESSOR PROTEIN P53;

EID: 77952550955     PISSN: 1044579X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.semcancer.2009.10.003     Document Type: Review

References (100)

1. Cahilly-Snyder L., Yang-Feng T., Francke U., George D.L. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat Cell Mol Genet 1987, 13:235-244.
2. Kussie P.H., Gorina S., Marechal V., Elenbaas B., Moreau J., Levine A.J., et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 1996, 274:948-953.
3. Momand J., Zambetti G.P., Olson D.C., George D., Levine A.J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992, 69:1237-1245.
4. Haupt Y., Maya R., Kazaz A., Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997, 387:296-299.
5. Honda R., Tanaka H., Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997, 420:25-27.
6. Tao W., Levine A.J. Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc Natl Acad Sci USA 1999, 96:3077-3080.
7. Wu X., Bayle J.H., Olson D., Levine A.J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993, 7:1126-1132.
8. Barak Y., Juven T., Haffner R., Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J 1993, 12:461-468.
9. Matheu A., Maraver A., Serrano M. The Arf/p53 pathway in cancer and aging. Cancer Res 2008, 68:6031-6034.
10. Dai M.S., Shi D., Jin Y., Sun X.X., Zhang Y., Grossman S.R., et al. Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism. J Biol Chem 2006, 281:24304-24313.
11. Jin A., Itahana K., O'Keefe K., Zhang Y. Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol 2004, 24:7669-7680.
12. Fang S., Jensen J.P., Ludwig R.L., Vousden K.H., Weissman A.M. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 2000, 275:8945-8951.
13. Meek D.W., Knippschild U. Posttranslational modification of MDM2. Mol Cancer Res 2003, 1:1017-1026.
14. Shvarts A., Steegenga W.T., Riteco N., van Laar T., Dekker P., Bazuine M., et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 1996, 15:5349-5357.
15. Ramos Y.F., Stad R., Attema J., Peltenburg L.T., van der Eb A.J., Jochemsen A.G. Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer Res 2001, 61:1839-1842.
16. Linares L.K., Hengstermann A., Ciechanover A., Muller S., Scheffner M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci USA 2003, 100:12009-12014.
17. Lane D. How cells choose to die. Nature 2001, 414:25-27.
18. Vousden K.H. Activation of the p53 tumor suppressor protein. Biochim Biophys Acta 2002, 14:47-59.
19. Momand J., Jung D., Wilczynski S., Niland J. The MDM2 gene amplification database. Nucleic Acids Res 1998, 26:3453-3459.
20. Bartel F., Meye A., Wurl P., Kappler M., Bache M., Lautenschlager C., et al. Amplification of the MDM2 gene, but not expression of splice variants of MDM2 MRNA, is associated with prognosis in soft tissue sarcoma. Intl J Cancer 2001, 95:168-175.
21. Boeckler F.M., Joerger A.C., Jaggi G., Rutherford T.J., Veprintsev D.B., Fersht A.R. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci USA 2008, 105:10360-10365.
22. Joerger A.C., Ang H.C., Fersht A.R. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci USA 2006, 103:15056-15061.
23. Myers M.C., Wang J., Iera J.A., Bang J.K., Hara T., Saito S., et al. A new family of small molecules to probe the reactivation of mutant p53. J Am Chem Soc 2005, 127:6152-6153.
24. Atencio I.A., Grace M., Bordens R., Fritz M., Horowitz J.A., Hutchins B., et al. Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial. Cancer Gene Ther 2006, 13:169-181.
25. Cristofanilli M., Krishnamurthy S., Guerra L., Broglio K., Arun B., Booser D.J., et al. A nonreplicating adenoviral vector that contains the wild-type p53 transgene combined with chemotherapy for primary breast cancer: safety, efficacy, and biologic activity of a novel gene-therapy approach. Cancer (Hoboken, NJ, United States) 2006, 107:935-944.
26. Fujiwara T., Tanaka N., Kanazawa S., Ohtani S., Saijo Y., Nukiwa T., et al. Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer. J Clin Oncol 2006, 24:1689-1699.
27. Guo J., Xin H. Chinese gene therapy. Splicing out the West?. Science 2006, 314:1232-1235.
28. Shimada H., Matsubara H., Shiratori T., Shimizu T., Miyazaki S., Okazumi S., et al. Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma. Cancer Sci 2006, 97:554-561.
29. Wallraven G., Nemunaitis J.J., Maples P.B. Compassionate approval process for experimental gene-based products. J Clin Oncol 2008, 26:1899-1900.
30. Mendrysa S.M., McElwee M.K., Michalowski J., O'Leary K.A., Young K.M., Perry M.E. Mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol 2003, 23:462-472.
31. Mendrysa S.M., O'Leary K.A., McElwee M.K., Michalowski J., Eisenman R.N., Powell D.A., et al. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev 2006, 20:16-21.
32. Zhang R., Wang H., Agrawal S. Novel antisense anti-MDM2 mixed-backbone oligonucleotides: proof of principle, in vitro and in vivo activities, and mechanisms. Curr Cancer Drug Targets 2005, 5:43-49.
33. O'Leary K.A., Mendrysa S.M., Vaccaro A., Perry M.E. Mdm2 regulates p53 independently of p19(ARF) in homeostatic tissues. Mol Cell Biol 2004, 24:186-191.
34. Vassilev L.T. MDM2 inhibitors for cancer therapy. Trends Mol Med 2007, 13:23-31.
35. Bogan A.A., Thorn K.S. Anatomy of hot spots in protein interfaces. J Mol Biol 1998, 280:1-9.
36. Fischer P.M. Peptide, peptidomimetic, and small-molecule antagonists of the p53-HDM2 protein-protein interaction. Int J Peptide Res Ther 2006, 12:3-19.
37. Hardcastle I.R. Inhibitors of the MDM2-p53 interaction as anticancer drugs. Drugs Fut 2007, 32:883-896.
38. Murray J.K., Gellman S.H. Targeting protein-protein interactions: lessons from p53/MDM2. Biopolymers 2007, 88:657-686.
39. Bottger V., Bottger A., Howard S.F., Picksley S.M., Chene P., Garcia-Echeverria C., et al. Identification of novel mdm2 binding peptides by phage display. Oncogene 1996, 13:2141-2147.
40. García-Echeverría C., Chène P., Blommers M.J.J., Furet P. Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53. J Med Chem 2000, 43:3205-3208.
41. Sakurai K., Schubert C., Kahne D. Crystallographic analysis of an 8-mer p53 peptide analogue complexed with MDM2. J Am Chem Soc 2006, 128:11000-11001.
42. Chene P., Fuchs J., Bohn J., García-Echeverría C., Furet P., Fabbro D. A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. J Mol Biol 2000, 299:245-253.
43. Shangary S., Wang S. Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res 2008, 14:5318-5324.
44. Hu C.-Q., Hu Y.-Z. Small molecule inhibitors of the p53-MDM2. Curr Med Chem 2008, 15:1720-1730.
45. Domling A. Small molecular weight protein-protein interaction antagonists: an insurmountable challenge?. Curr Opin Chem Biol 2008, 12:281-291.
46. Dey A., Verma C.S., Lane D.P. Updates on p53: modulation of p53 degradation as a therapeutic approach. Br J Cancer 2008, 98:4-8.
47. Berg T. Small-molecule inhibitors of protein-protein interactions. Curr Opin Drug Discov Dev 2008, 11:666-674.
48. Vassilev L.T., Vu B.T., 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, 303:844-848.
49. Koblish H.K., Zhao S., Franks C.F., Donatelli R.R., Tominovich R.M., LaFrance L.V., 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, 5:160-169.
50. Leonard K., Marugan J.J., Raboisson P., Calvo R., Gushue J.M., Koblish H.K., et al. Novel 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists with improved cellular activity. Bioorg Med Chem Lett 2006, 16:3463-3468.
51. Marugan J.J., Leonard K., Raboisson P., Gushue J.M., Calvo R., Koblish H.K., et al. Enantiomerically pure 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists. Bioorg Med Chem Lett 2006, 16:3115-3120.
52. Parks D.J., Lafrance L.V., Calvo R.R., Milkiewicz K.L., Gupta V., Lattanze J., 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, 15:765-770.
53. Parks D.J., LaFrance L.V., Calvo R.R., Milkiewicz K.L., Jose Marugan J., Raboisson P. 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, 16:3310-3314.
54. Ding K., Lu Y., Nikolovska-Coleska Z., Qiu S., Ding Y., Gao W., et al. Structure-based design of potent non-peptide MDM2 inhibitors. J Am Chem Soc 2005, 127:10130-10131.
55. Ding K., Lu Y., Nikolovska-Coleska Z., Wang G., Qiu S., Shangary S., et al. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 2006, 49:3432-3435.
56. Deng J., Dayam R., Neamati N. Patented small molecule inhibitors of p53-MDM2 interaction. Expert Opin Ther Pat 2006, 16:165-188.
57. Uhrinova S., Uhrin D., Powers H., Watt K., Zheleva D., Fischer P., et al. Structure of Free MDM2 N-terminal domain reveals conformational adjustments that accompany p53-binding. J Mol Biol 2005, 350:587-598.
58. Showalter S.A., Bruschweiler-Li L., Johnson E., Zhang F., Bruschweiler R. Quantitative lid dynamics of MDM2 reveals differential ligand binding modes of the p53-binding cleft. J Am Chem Soc 2008, 130:6472-6478.
59. Shangary S., Qin D., McEachern D., Liu M., Miller R.S., 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 USA 2008, 105:3933-3938.
60. Hu B., Gilkes D.M., Farooqi B., Sebti S.M., Chen J. MDMX overexpression prevents p53 activation by the MDM2 inhibitor nutlin. J Biol Chem 2006, 281:33030-33035.
61. Patton J.T., Mayo L.D., Singhi A.D., Gudkov A.V., Stark G.R., Jackson M.W. Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Res 2006, 66:3169-3176.
62. Hu B., Gilkes D.M., Chen J. Efficient p53 activation and apoptosis by simultaneous disruption of binding to MDM2 and MDMX. Cancer Res 2007, 67:8810-8817.
63. Popowicz G.M., Czarna A., Holak T.A. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle 2008, 7:2441-2443.
64. Popowicz G.M., Czarna A., Rothweiler U., Sszwagierczak A., Krajewski M., Weber L., et al. Molecular Basis for the Inhibition of p53 by Mdmx. Cell Cycle 2007, 6:2386-2392.
65. Macchiarulo A., Giacche N., Carotti A., Baroni M., Cruciani G., Pellicciari R. Targeting the conformational transitions of MDM2 and MDMX: insights into dissimilarities and similarities of p53 recognition. J Chem Inf Model 2008, ePub ahead of print (doi:10.1021/ci800146m).
66. McCoy M.A., Gesell J.J., Senior M.M., Wyss D.F. Flexible lid to the p53-binding domain of human Mdm2: implications for p53 regulation. Proc Natl Acad Sci USA 2003, 100:1645-1648.
67. Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J 1998, 17:7151-7160.
68. Fang S., Weissman A.M. A field guide to ubiquitinylation. Cell Mol Life Sci 2004, 61:1546-1561.
69. Joazeiro C.A., Weissman A.M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 2000, 102:549-552.
70. Grossman S.R., Deato M.E., Brignone C., Chan H.M., Kung A.L., Tagami H., et al. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 2003, 300:342-344.
71. Li M., Brooks C.L., Wu-Baer F., Chen D., Baer R., Gu W. Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 2003, 302:1972-1975.
72. Lai Z., Ferry K.V., Diamond M.A., Wee K.E., Kim Y.B., Ma J., et al. Human mdm2 mediates multiple mono-ubiquitination of p53 by a mechanism requiring enzyme isomerization. J Biol Chem 2001, 276:31357-31367.
73. Leng R.P., Lin Y., Ma W., Wu H., Lemmers B., Chung S., et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 2003, 112:779-791.
74. Dornan D., Wertz I., Shimizu H., Arnott D., Frantz G.D., Dowd P., et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 2004, 429:86-92.
75. Chen D., Kon N., Li M., Zhang W., Qin J., Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 2005, 121:1071-1083.
76. Lai Z., Yang T., Kim Y.B., Sielecki T.M., Diamond M.A., Strack P., et al. Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors. Proc Natl Acad Sci USA 2002, 99:14734-14739.
77. Ma J., Martin J.D., Zhang H., Auger K.R., Ho T.F., Kirkpatrick R.B., et al. A second p53 binding site in the central domain of Mdm2 is essential for p53 ubiquitination. Biochemistry 2006, 45:9238-9245.
78. Murray M.F., Jurewicz A.J., Martin J.D., Ho T.F., Zhang H., Johanson K.O., et al. A high-throughput screen measuring ubiquitination of p53 by human mdm2. J Biomol Screen 2007, 12:1050-1058.
79. Davydov I.V., Woods D., Safiran Y.J., Oberoi P., Fearnhead H.O., Fang S., et al. Assay for ubiquitin ligase activity: high-throughput screen for inhibitors of HDM2. J Biomol Screen 2004, 9:695-703.
80. Yang Y., Ludwig R.L., Jensen J.P., Pierre S.A., Medaglia M.V., Davydov I.V., et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 2005, 7:547-559.
81. Burgstaller P., Hermann T., Huber C., Westhof E., Famulok M. Isoalloxazine derivatives promote photocleavage of natural RNAs at G.U base pairs embedded within helices. Nucleic Acids Res 1997, 25:4018-4027.
82. Kawamoto T., Ikeuchi Y., Hiraki J., Eikyu Y., Shimizu K., Tomishima M., et al. Synthesis and evaluation of nitro 5-deazaflavins as novel bioreductive antitumor agents. Bioorg Med Chem Lett 1995, 5:2109-2114.
83. Kawamoto T., Ikeuchi Y., Hiraki J., Eikyu Y., Shimizu K., Tomishima M., et al. Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins. Bioorg Med Chem Lett 1995, 5:2115-2118.
84. Wilson J.M., Henderson G., Black F., Sutherland A., Ludwig R.L., Vousden K.H., et al. Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells. Bioorg Med Chem 2007, 15:77-86.
85. Kitagaki J., Agama K.K., Pommier Y., Yang Y., Weissman A.M. Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2. Mol Cancer Ther 2008, 7:2445-2454.
86. Sasiela C.A., Stewart D.H., Kitagaki J., Safiran Y.J., Yang Y., Weissman A.M., et al. Identification of inhibitors for MDM2 ubiquitin ligase activity from natural product extracts by a novel high-throughput electrochemiluminescent screen. J Biomol Screen 2008, 13:229-237.
87. Woodward R.B., Witkop B. The structure of sempervirine. J Am Chem Soc 1949, 71:379.
88. Beljanski M., Beljanski M.S. Three alkaloids as selective destroyers of cancer cells in mice. Synergy with classic anticancer drugs. Oncology 1986, 43:198-203.
89. Wang W., Ho W.C., Dicker D.T., MacKinnon C., Winkler J.D., Marmorstein R., et al. Acridine derivatives activate p53 and induce tumor cell death through Bax. Cancer Biol Ther 2005, 4:893-898.
90. Poyurovsky M.V., Priest C., Kentsis A., Borden K.L., Pan Z.Q., Pavletich N., et al. The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J 2007, 26:90-101.
91. Uldrijan S., Pannekoek W.J., Vousden K.H. An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J 2007, 26:102-112.
92. Linke K., Mace P.D., Smith C.A., Vaux D.L., Silke J., Day C.L. Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitinylation in trans. Cell Death Differ 2008, 15:841-848.
93. Kostic M., Matt T., Martinez-Yamout M.A., Dyson H.J., Wright P.E. Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53. J Mol Biol 2006, 363:433-450.
94. Arts J., Page M., Valckx A., Blattner C., Kulikov R., Floren W., et al. JNJ-26854165-a novel hdm2 antagonist in clinical development showing broad-spectrum preclinical antitumor activity against solid malignancies. Proc Am Assoc Cancer Res 2008, 49. Abs. 1592.
95. Roche Pharma Pipeline; 2008. http://www.roche.com/pipeline.htm.
96. Ascenta's Pipeline; 2008. http://www.ascenta.com/.
97. Garber K. Missing the target: ubiquitin ligase drugs stall. J Natl Cancer Inst 2005, 97:166-167.
98. Fry D.C., Emerson S.D., Palme S., Vu B.T., Liu C.-M., Podlaski F. NMR structure of a complex between MDM2 and a small molecule inhibitor. J Biomol NMR 2004, 30:163-173.
99. Grasberger B.L., Lu T., Schubert C., Parks D.J., Carver T.E., Koblish H.K., et al. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem 2005, 48:909-912.
100. Fasan R., Dias R.L., Moehle K., Zerbe O., Obrecht D., Mittl P.R., et al. Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction. ChemBioChem 2006, 7:515-526.