Targeting p53-MDM2-MDMX loop for cancer therapy

Sub-Cellular Biochemistry

Volumn 85, Issue , 2014, Pages 281-319

  Zhang, Qi ^a   Zeng, Shelya X ^a   Lu, Hua ^a  

^a TULANE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer therapy; Drug design; Drug development; Drug discovery; MDM2; MDMX; p53

Indexed keywords

ANTINEOPLASTIC AGENT; MDM2 PROTEIN, HUMAN; MDM4 PROTEIN, HUMAN; NUCLEAR PROTEIN; ONCOPROTEIN; PROTEIN MDM2;

ANTAGONISTS AND INHIBITORS; GENETICS; HUMAN; NEOPLASMS; PHYSIOLOGY; TUMOR SUPPRESSOR GENE;

ANTINEOPLASTIC AGENTS; GENES, P53; HUMANS; NEOPLASMS; NUCLEAR PROTEINS; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-MDM2;

EID: 84914693610     PISSN: 03060225     EISSN: None     Source Type: Journal    
DOI: 10.1007/978-94-017-9211-0_16     Document Type: Article

References (183)

1. Brown CJ et al (2009) Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9(12): 862-873.
2. Kruse JP, Gu W (2009) Modes of p53 regulation. Cell 137(4): 609-622.
3. Hollstein M et al (1991) p53 mutations in human cancers. Science 253(5015): 49-53.
4. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408(6810): 307-310.
5. Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3): 413-431.
6. Hong H et al (2009) Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460(7259): 1132-1135.
7. Wu X et al (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7(7A): 1126-1132.
8. Momand J et al (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69(7): 1237-1245.
9. Barak Y et al (1993) mdm2 expression is induced by wild type p53 activity. EMBO J 12(2): 461-468.
10. Shvarts A et al (1996) MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 15(19): 5349-5357.
11. Eischen CM, Lozano G (2009) p53 and MDM2: antagonists or partners in crime? Cancer Cell 15(3): 161-162.
12. Gu J et al (2002) Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 277(22): 19251-19254.
13. Haupt Y et al (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630): 296-299.
14. Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387(6630): 299-303.
15. Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420(1): 25-27.
16. Wade M, Li YC, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13(2): 83-96.
17. Gembarska A et al (2012) MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 18(8): 1239-1247.
18. Biderman L et al (2012) MdmX is required for p53 interaction with and full induction of the Mdm2 promoter after cellular stress. Mol Cell Biol 32(7): 1214-1225.
19. Wade M, Wahl GM (2009) Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res 7(1): 1-11.
20. Zhang Y, Lu H (2009) Signaling to p53: ribosomal proteins find their way. Cancer Cell 16(5): 369-377.
21. Wade M, Wang YV, Wahl GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 20(5): 299-309.
22. Garcia D et al (2011) Validation of MdmX as a therapeutic target for reactivating p53 in tumors. Genes Dev 25(16): 1746-1757.
23. Tang Y et al (2008) Acetylation is indispensable for p53 activation. Cell 133(4): 612-626.
24. Shieh SY et al (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91(3): 325-334.
25. Banin S et al (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281(5383): 1674-1677.
26. Maya R et al (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15(9): 1067-1077.
27. Kapoor M, Lozano G (1998) Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. Proc Natl Acad Sci U S A 95(6): 2834-2837.
28. Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92(6): 725-734.
29. Kobet E et al (2000) MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins. Proc Natl Acad Sci U S A 97(23): 12547-12552.
30. Li M et al (2002) Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 277(52): 50607-50611.
31. Ito A et al (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20(6): 1331-1340.
32. Luo J et al (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107(2): 137-148.
33. Vaziri H et al (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107(2): 149-159.
34. Cheng HL et al (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A 100(19): 10794-10799.
35. Luo J et al (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408(6810): 377-381.
36. Onel K, Cordon-Cardo C (2004) MDM2 and prognosis. Mol Cancer Res 2(1): 1-8.
37. Nosho K et al (2009) SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Mod Pathol 22(7): 922-932.
38. Jung-Hynes B et al (2009) Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J Biol Chem 284(6): 3823-3832.
39. Ozdag H et al (2006) Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics 7: 90.
40. Tseng RC et al (2009) Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia 11(8): 763-770.
41. Jones SN et al (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378(6553): 206-208.
42. Montes de Oca Luna R, Wagner DS, Lozano G (1995) Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378(6553): 203-206.
43. Gannon HS, Jones SN (2012) Using mouse models to explore MDM-p53 signaling in development, cell growth, and tumorigenesis. Genes Cancer 3(3-4): 209-218.
44. Vassilev LT et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659): 844-848.
45. Chargari C et al (2011) Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts. Cancer Lett 312(2): 209-218.
46. Kojima K et al (2010) The novel tryptamine derivative JNJ-26854165 induces wild-type p53-and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias. Mol Cancer Ther 9(9): 2545-2557.
47. Yang Y et al (2005) Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7(6): 547-559.
48. Roxburgh P et al (2012) Small molecules that bind the Mdm2 RING stabilize and activate p53. Carcinogenesis 33(4): 791-798.
49. Herman AG et al (2011) Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay. Cancer Discov 1(4): 312-325.
50. Galatin PS, Abraham DJ (2004) A nonpeptidic sulfonamide inhibits the p53-mdm2 interaction and activates p53-dependent transcription in mdm2-overexpressing cells. J Med Chem 47(17): 4163-4165.
51. Lu Y et al (2006) Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy. J Med Chem 49(13): 3759-3762.
52. Yin H et al (2005) Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction. Angew Chem Int Ed Engl 44(18): 2704-2707.
53. Hardcastle IR et al (2006) Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. J Med Chem 49(21): 6209-6221.
54. Hardcastle IR et al (2011) Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency. J Med Chem 54(5): 1233-1243.
55. Koblish HK et al (2006) Benzodiazepinedione inhibitors of the Hdm2: p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 5(1): 160-169.
56. Schilling D et al (2013) Radiosensitization of wildtype p53 cancer cells by the MDM2-inhibitor PXN727 is associated with altered heat shock protein 70 (Hsp70) levels. Cell Stress Chaperones 18(2): 183-191.
57. Cheok CF et al (2011) Translating p53 into the clinic. Nat Rev Clin Oncol 8(1): 25-37.
58. Bista M et al (2012) On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53. PLoS One 7(6): e37518.
59. Reed D et al (2010) Identification and characterization of the first small molecule inhibitor of MDMX. J Biol Chem 285(14): 10786-10796.
60. Wang H et al (2011) A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Mol Cancer Ther 10(1): 69-79.
61. Graves B et al (2012) Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci U S A 109(29): 11788-11793.
62. Qin JJ et al (2012) Natural product MDM2 inhibitors: anticancer activity and mechanisms of action. Curr Med Chem 19(33): 5705-5725.
63. Zak K et al (2013) Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011-present). Expert Opin Ther Pat 23(4): 425-448.
64. Kamal A, Mohammed AA, Shaik TB (2012) p53-Mdm2 inhibitors: patent review (2009-2010). Expert Opin Ther Pat 22(2): 95-105.
65. Weber L (2010) Patented inhibitors of p53-Mdm2 interaction (2006-2008). Expert Opin Ther Pat 20(2): 179-191.
66. Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90(4): 595-606.
67. Gu W, Shi XL, Roeder RG (1997) Synergistic activation of transcription by CBP and p53. Nature 387(6635): 819-823.
68. Li L et al (2012) Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21(2): 266-281.
69. Zhang Q et al (2012) A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53. EMBO Mol Med 4(4): 298-312.
70. Lain S et al (2008) Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13(5): 454-463.
71. Kim WJ et al (2012) The WTX tumor suppressor enhances p53 acetylation by CBP/p300. Mol Cell 45(5): 587-597.
72. Kussie PH et al (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274(5289): 948-953.
73. Joseph TL et al (2010) Differential binding of p53 and nutlin to MDM2 and MDMX: computational studies. Cell Cycle 9(6): 1167-1181.
74. Almerico AM et al (2012) Molecular dynamics studies on Mdm2 complexes: an analysis of the inhibitor influence. Biochem Biophys Res Commun 424(2): 341-347.
75. Tsuganezawa K et al (2013) A fluorescent-based high-throughput screening assay for small molecules that inhibit the interaction of MdmX with p53. J Biomol Screen 18(2): 191-198.
76. Grasberger BL et al (2005) Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem 48(4): 909-912.
77. Popowicz GM, Domling A, Holak TA (2011) The structure-based design of Mdm2/Mdmx-p53 inhibitors gets serious. Angew Chem Int Ed Engl 50(12): 2680-2688.
78. Pazgier M et al (2009) Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A 106(12): 4665-4670.
79. Liu M et al (2010) D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms. Proc Natl Acad Sci U S A 107(32): 14321-14326.
80. Zhan C et al (2012) An ultrahigh affinity d-peptide antagonist Of MDM2. J Med Chem 55(13): 6237-6241.
81. Sasiela CA et al (2008) Identification of inhibitors for MDM2 ubiquitin ligase activity from natural product extracts by a novel high-throughput electrochemiluminescent screen. J Biomol Screen 13(3): 229-237.
82. Murray MF et al (2007) A high-throughput screen measuring ubiquitination of p53 by human mdm2. J Biomol Screen 12(8): 1050-1058.
83. Dudgeon DD et al (2010) Implementation of a 220, 000-compound HCS campaign to identify disruptors of the interaction between p53 and hDM2 and characterization of the confirmed hits. J Biomol Screen 15(7): 766-782.
84. Dudgeon DD et al (2010) Characterization and optimization of a novel protein-protein interaction biosensor high-content screening assay to identify disruptors of the interactions between p53 and hDM2. Assay Drug Dev Technol 8(4): 437-458.
85. Khoury K et al (2011) The p53-MDM2/MDMX axis-a chemotype perspective. Med Chem Commun 2(4): 246-260.
86. Popowicz GM et al (2010) Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle 9(6): 1104-1111.
87. Bernal F et al (2007) Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc 129(9): 2456-2457.
88. Bernal F et al (2010) A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18(5): 411-422.
89. Huang Y et al (2010) 1, 4-Thienodiazepine-2, 5-diones via MCR (I): synthesis, virtual space and p53-Mdm2 activity. Chem Biol Drug Des 76(2): 116-129.
90. Lee JH et al (2011) Novel pyrrolopyrimidine-based alpha-helix mimetics: cell-permeable inhibitors of protein-protein interactions. J Am Chem Soc 133(4): 676-679.
91. Czarna A et al (2010) Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists. Angew Chem Int Ed Engl 49(31): 5352-5356.
92. Fu T et al (2012) Molecular dynamic simulation insights into the normal state and restoration of p53 function. Int J Mol Sci 13(8): 9709-9740.
93. Ding K et al (2006) Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 49(12): 3432-3435.
94. Shangary S et al (2008) 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 105(10): 3933-3938.
95. Yu S et al (2009) Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 52(24): 7970-7973.
96. Rew Y et al (2012) Structure-based design of novel inhibitors of the MDM2-p53 interaction. J Med Chem 55(11): 4936-4954.
97. Lucas BS et al (2012) An expeditious synthesis of the MDM2-p53 inhibitor AM-8553. J Am Chem Soc 134(30): 12855-12860.
98. Bowman AL et al (2007) Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models. J Am Chem Soc 129(42): 12809-12814.
99. Jacoby E et al (2009) Knowledge-based virtual screening: application to the MDM4/p53 protein-protein interaction. Methods Mol Biol 575: 173-194.
100. Tovar C et al (2013) MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 73(8): 2587-2597.
101. Ray-Coquard I et al (2012) 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 13(11): 1133-1140.
102. Andreeff M et al (2012) Results of the phase 1 trial of RG7112, a small-molecule MDM2 antagonist, in acute leukemia. In: 54 annual meeting American Society of Hematology, Atlanta, 8-11 Dec 2012, p 615, Abstract 675.
103. Wang S et al (2012) Targeting the MDM2-p53 protein-protein interaction for new cancer therapeutics. Top Med Chem 8: 57-80.
104. Mohammad RM et al (2009) An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals. Mol Cancer 8: 115.
105. Menendez S et al (2011) MDM4 downregulates p53 transcriptional activity and response to stress during differentiation. Cell Cycle 10(7): 1100-1108.
106. Laurie NA, Schin-Shih C, Dyer MA (2007) Targeting MDM2 and MDMX in retinoblastoma. Curr Cancer Drug Targets 7(7): 689-695.
107. Smith MA et al (2012) Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program. Pediatr Blood Cancer 59(2): 329-332.
108. Honda R, Yasuda H (1999) Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 18(1): 22-27.
109. Weber JD et al (1999) Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1(1): 20-26.
110. Kamijo T et al (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 95(14): 8292-8297.
111. Bothner B et al (2001) Defining the molecular basis of Arf and Hdm2 interactions. J Mol Biol 314(2): 263-277.
112. Sivakolundu SG et al (2008) Intrinsically unstructured domains of Arf and Hdm2 form bimolecular oligomeric structures in vitro and in vivo. J Mol Biol 384(1): 240-254.
113. DiGiammarino EL et al (2001) Solution structure of the p53 regulatory domain of the p19Arf tumor suppressor protein. Biochemistry 40(8): 2379-2386.
114. Weber JD et al (2000) Cooperative signals governing ARF-mdm2 interaction and nucleolar localization of the complex. Mol Cell Biol 20(7): 2517-2528.
115. Zhou X et al (2012) Scission of the p53-MDM2 loop by ribosomal proteins. Genes Cancer 3(3-4): 298-310.
116. Zhang Q et al (2011) Hydrophilic residues are crucial for ribosomal protein L11 (RPL11) interaction with zinc finger domain of MDM2 and p53 protein activation. J Biol Chem 286(44): 38264-38274.
117. Dai MS et al (2006) Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism. J Biol Chem 281(34): 24304-24313.
118. Bhat KP et al (2004) Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation. EMBO J 23(12): 2402-2412.
119. Zhang Y et al (2003) Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 23(23): 8902-8912.
120. Imai S (2007) Is Sirt1 a miracle bullet for longevity? Aging Cell 6(6): 735-737.
121. Chen D et al (2005) Increase in activity during calorie restriction requires Sirt1. Science 310(5754): 1641.
122. Stunkel W et al (2007) Function of the SIRT1 protein deacetylase in cancer. Biotechnol J 2(11): 1360-1368.
123. Inoue Y et al (2011) Suppression of p53 activity through the cooperative action of Ski and histone deacetylase SIRT1. J Biol Chem 286(8): 6311-6320.
124. Chen WY et al (2005) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123(3): 437-448.
125. Blum CA et al (2011) SIRT1 modulation as a novel approach to the treatment of diseases of aging. J Med Chem 54(2): 417-432.
126. Chakrabarty SP, Balaram H, Chandrasekaran S (2011) Sirtuins: multifaceted drug targets. Curr Mol Med 11(9): 709-718.
127. Balcerczyk A, Pirola L (2010) Therapeutic potential of activators and inhibitors of sirtuins. Biofactors 36(5): 383-393.
128. Zhang Y et al (2012) Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth. Cancer Biol Ther 13(10): 915-924.
129. Yiwei Z, Zhang Q, Zeng SX, Qian Hao, Hua Lu (2013) Inauhzin sensitizes p53-dependent cytotoxicity and tumor suppression of chemotherapeutic agents. Neoplasia 15(5): 523-534.
130. Zhang Q et al (2012) Structure and activity analysis of Inauhzin analogs as novel antitumor compounds that induce p53 and inhibit cell growth. PLoS One 7(10): e46294.
131. Liao JM et al (2012) Global effect of inauhzin on human p53-responsive transcriptome. PLoS One 7(12): e52172.
132. Azmi AS et al (2011) Network perspectives on HDM2 inhibitor chemotherapy combinations. Curr Pharm Des 17(6): 640-652.
133. Azmi AS et al (2010) MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function. Eur J Cancer 46(6): 1122-1131.
134. Zheng T et al (2010) Nutlin-3 cooperates with doxorubicin to induce apoptosis of human hepatocellular carcinoma cells through p53 or p73 signaling pathways. J Cancer Res Clin Oncol 136(10): 1597-1604.
135. Koster R et al (2011) Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death Dis 2: e148.
136. Michaelis M et al (2011) Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis 2: e243.
137. Muller PA, Vousden KH (2013) p53 mutations in cancer. Nat Cell Biol 15(1): 2-8.
138. Long J et al (2010) Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood 116(1): 71-80.
139. Laurie NA et al (2006) Inactivation of the p53 pathway in retinoblastoma. Nature 444(7115): 61-66.
140. Clegg HV et al (2012) Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction. PLoS One 7(5): e38212.
141. Huang L et al (2011) The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci U S A 108(29): 12001-12006.
142. Itahana K et al (2007) Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12(4): 355-366.
143. Di J, Zhang Y, Zheng J (2011) Reactivation of p53 by inhibiting Mdm2 E3 ligase: a novel antitumor approach. Curr Cancer Drug Targets 11(8): 987-994.
144. Maslon MM, Hupp TR (2010) Drug discovery and mutant p53. Trends Cell Biol 20(9): 542-555.
145. Bykov VJ et al (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8(3): 282-288.
146. Mohell N et al (2010) Preclinical efficacy and toxicology studies of APR-246, a novel anticancer compound currently in clinical trials for refractory hematological malignancies and prostate cancer. Blood 116(21).
147. Lehmann S et al (2012) Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol 30(29): 3633-3639.
148. Shalom-Feuerstein R et al (2013) Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc Natl Acad Sci U S A 110(6): 2152-2156.
149. Yu X et al (2012) Allele-specific p53 mutant reactivation. Cancer Cell 21(5): 614-625.
150. Lawrence HR et al (2009) Identification of a disruptor of the MDM2-p53 protein-protein interaction facilitated by high-throughput in silico docking. Bioorg Med Chem Lett 19(14): 3756-3759.
151. Parks DJ et al (2005) 1, 4-Benzodiazepine-2, 5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR. Bioorg Med Chem Lett 15(3): 765-770.
152. Zhuang C et al (2012) Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction. J Med Chem 55(22): 9630-9642.
153. Krajewski M et al (2005) NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro. Nat Med 11(11): 1135-1136; author reply 1136-7.
154. Issaeva N et al (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10(12): 1321-1328.
155. Michel J et al (2009) In Silico Improvement of beta3-peptide inhibitors of p53 x hDM2 and p53 x hDMX. J Am Chem Soc 131(18): 6356-6357.
156. Palani CD, Beck JF, Sonnemann J (2012) Histone deacetylase inhibitors enhance the anticancer activity of nutlin-3 and induce p53 hyperacetylation and downregulation of MDM2 and MDM4 gene expression. Invest New Drugs 30(1): 25-36.
157. Zauli G et al (2012) The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status. Haematologica 97(11): 1722-1730.
158. Vatsyayan R et al (2013) Nutlin-3 enhances sorafenib efficacy in renal cell carcinoma. Mol Carcinog 52(1): 39-48.
159. Weisberg E, Sattler M (2012) A novel combination therapy approach for the treatment of acute myeloid leukemia: the multi-kinase inhibitor sorafenib and the HDM2 inhibitor nutlin-3. Haematologica 97(11): 1620-1621.
160. Vaseva AV et al (2011) Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors. Cell Death Dis 2: e156.
161. Zauli G et al (2011) Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. Clin Cancer Res 17(4): 762-770.
162. Kurosu T et al (2010) Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway. Apoptosis 15(5): 608-620.
163. Cheok CF et al (2010) Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ 17(9): 1486-1500.
164. Azmi AS et al (2011) MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene 30(1): 117-126.
165. Carter BZ et al (2010) Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML. Blood 115(2): 306-314.
166. Ooi MG et al (2009) Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib. Clin Cancer Res 15(23): 7153-7160.
167. Tabe Y et al (2009) MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin Cancer Res 15(3): 933-942.
168. Jin L et al (2010) MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma. Cancer Lett 299(2): 161-170.
169. Cross B et al (2011) Inhibition of p53 DNA binding function by the MDM2 protein acidic domain. J Biol Chem 286(18): 16018-16029.
170. Secchiero P et al (2011) Recent advances in the therapeutic perspectives of Nutlin-3. Curr Pharm Des 17(6): 569-577.
171. Saha MN et al (2010) MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 9(11): 936-944.
172. McCormack E et al (2012) Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia 26(5): 910-917.
173. Kojima K et al (2006) Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle 5(23): 2778-2786.
174. Kojima K et al (2008) Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia. Blood 112(7): 2886-2895.
175. Kojima K et al (2008) The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 22(9): 1728-1736.
176. Ohgami T et al (2010) Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers. Cancer Sci 101(6): 1387-1395.
177. Endo S et al (2011) Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells. Cancer Sci 102(3): 605-613.
178. Mir R et al (2013) Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells. Int J Cancer 132(7): 1525-1536.
179. D'Anneo A et al (2010) Paclitaxel and beta-lapachone synergistically induce apoptosis in human retinoblastoma Y79 cells by downregulating the levels of phospho-Akt. J Cell Physiol 222(2): 433-443.
180. Cheok CF, Dey A, Lane DP (2007) Cyclin-dependent kinase inhibitors sensitize tumor cells to nutlin-induced apoptosis: a potent drug combination. Mol Cancer Res 5(11): 1133-1145.
181. Hu B et al (2006) MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem 281(44): 33030-33035.
182. Nadler-Milbauer M et al (2011) Synchronized release of Doxil and Nutlin-3 by remote degradation of polysaccharide matrices and its possible use in the local treatment of colorectal cancer. J Drug Target 19(10): 859-873.
183. Jones RJ et al (2011) HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma. Blood 118(15): 4140-4149.