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Anticancer strategies by upregulating p53 through inhibition of its ubiquitination by MDM2

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Abstract

The potentiation of p53 activity through inhibition of its negative regulator MDM2 is an attractive strategy for anticancer therapy. Much progress has been made in the last decade in a diverse range of areas related to p53 and MDM2. This review focuses on the recent progress in developing small-molecule inhibitors of the MDM2 protein by covering the following approaches that inhibit the function of the p53–MDM2 axis: (1) direct binding to MDM2, (2) direct binding to p53, (3) targeted degradation of MDM2 by the PROTAC approach, and (4) inhibition of MDM2/MDM4 interaction. Given the importance of p53 in cancer development, we hope that research in this area will lead to anticancer drugs in the not too distant future.

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References

  • Al-Fatlawi AA, Al-fatlawi AA, Zafaryab M, Irshad M, Ahmad I, Kazim Z, Ahmad A, Rizvi MMA (2014) Rhein induced cell death and apoptosis through caspase dependent and associated with modulation of p53, bcl-2/bax ratio in human cell lines. Int J Pharm Pharm Sci 6:215219

    Google Scholar 

  • Andreeff M, Kelly KR, Yee K, Assouline S, Strair R, Popplewell L, Bowen D, Martinelli G, Drummond MW, Vyas P (2016) Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res 22:868–876

    CAS  PubMed  Google Scholar 

  • Anifowose A, Agbowuro AA, Tripathi R, Lu W, Tan C, Yang X, Wang B (2020a) Inducing apoptosis through upregulation of p53: structure-activity exploration of anthraquinone analogs. Med Chem Res (Accepted manuscript)

  • Anifowose A, Yuan Z, Yang X, Pan Z, Zheng Y, Zhang Z, Wang B (2020b) Upregulation of p53 through induction of MDM2 degradation: amino acid prodrugs of anthraquinone analogs. Bioorg Med Chem Lett 30:126786

    PubMed  Google Scholar 

  • Asher G, Lotem J, Sachs L, Kahana C, Shaul Y (2002) Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. Proc Natl Acad Sci USA 99:13125–13130

    CAS  PubMed  PubMed Central  Google Scholar 

  • Baek K, Schulman BA (2020) Molecular glue concept solidifies. Nat Chem Biol 16:2–3

    CAS  PubMed  Google Scholar 

  • Bernal F, Tyler AF, Korsmeyer SJ, Walensky LD, Verdine GL (2007) Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc 129:2456–2457

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bernal F, Wade M, Godes M, Davis TN, Whitehead DG, Kung AL, Wahl GM, Walensky LD (2010) A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer cell 18:411–422

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bernard D, Zhao Y, Wang S (2012) AM-8553: a novel MDM2 inhibitor with a promising outlook for potential clinical development. J Med Chem 55:4934–4935

    CAS  PubMed  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    PubMed  Google Scholar 

  • Brooks CL, Gu W (2006) p53 ubiquitination: Mdm2 and beyond. Mol Cell 21:307–315

    CAS  PubMed  PubMed Central  Google Scholar 

  • Burslem GM, Smith BE, Lai AC, Jaime-Figueroa S, McQuaid DC, Bondeson DP, Toure M, Dong H, Qian Y, Wang J, Crew AP, Hines J, Crews CM (2018) The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem Biol 25:67–77 e63

    CAS  PubMed  Google Scholar 

  • Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To K-H, Olson KA, Kesavan K, Gangurde P, Mukherjee A (2013a) Stapled α− helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA 110:E3445–E3454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To K-H, Olson KA, Kesavan K, Gangurde P, Mukherjee A (2013b) Stapled α− helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA 110:E3445–E3454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To KH, Olson KA, Kesavan K, Gangurde P, Mukherjee A, Baker T, Darlak K, Elkin C, Filipovic Z, Qureshi FZ, Cai H, Berry P, Feyfant E, Shi XE, Horstick J, Annis DA, Manning AM, Fotouhi N, Nash H, Vassilev LT, Sawyer TK (2013c) Stapled alpha-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA 110:E3445–3454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheok CF, Verma CS, Baselga J, Lane DP (2011) Translating p53 into the clinic (vol 8, pg 25, 2011). Nat Rev Clin Oncol 8:568–568

    Google Scholar 

  • Churcher I (2017) Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J Med Chem 61:444–452

    PubMed  Google Scholar 

  • Crews CM (2018) Inducing protein degradation as a therapeutic strategy. J Med Chem 61:403–404

    CAS  PubMed  Google Scholar 

  • Dang CV, Reddy EP, Shokat KM, Soucek L (2017) Drugging the’undruggable’cancer targets. Nat Rev Cancer 17:502

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Weger VA, de Jonge M, Langenberg MH, Schellens JH, Lolkema M, Varga A, Demers B, Thomas K, Hsu K, Tuffal G (2019) A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. Br J Cancer 120:286

    PubMed  Google Scholar 

  • Deb SP (2002) Function and dysfunction of the human oncoprotein MDM2. Front Biosci 7:d235–d243

    CAS  PubMed  Google Scholar 

  • DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ (1979) Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci USA 76:2420–2424

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding Y, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y (2005) Structure-based design of potent non-peptide MDM2 inhibitors. J Am Chem Soc 127:10130–10131

    CAS  PubMed  Google Scholar 

  • Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S, Gao W, Qin D, Stuckey J, Krajewski K (2006) Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2− p53 interaction. J Med Chem 49:3432–3435

    CAS  PubMed  Google Scholar 

  • Ding Q, Zhang Z, Liu J-J, Jiang N, Zhang J, Ross TM, Chu X-J, Bartkovitz D, Podlaski F, Janson C (2013) Discovery of RG7388, a potent and selective p53–MDM2 inhibitor in clinical development. J Med Chem 56:5979–5983

    CAS  PubMed  Google Scholar 

  • Draganov AB, Yang X, Anifowose A, De La Cruz LKC, Dai C, Ni N, Chen W, De Los Santos Z, Gu L, Zhou M, Wang B (2019) Upregulation of p53 through induction of MDM2 degradation: anthraquinone analogs. Bioorg Med Chem 27:3860–3865

    CAS  PubMed  Google Scholar 

  • Erba HP, Becker PS, Shami PJ, Grunwald MR, Flesher DL, Zhu M, Rasmussen E, Henary HA, Anderson AA, Wang ES (2019) Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv 3:1939–1949

    PubMed  PubMed Central  Google Scholar 

  • Espadinha M, Barcherini V, Lopes EA, Santos MMM (2018) An update on MDMX and dual MDM2/X inhibitors. Curr Top Med Chem 18:647–660

    CAS  PubMed  Google Scholar 

  • Fang Y, Liao G, Xu B (2020) Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharm Sinica B (in press) https://doi.org/10.1016/j.apsb.2020.1001.1003

  • Forslund A, Zeng Z, Qin L-X, Rosenberg S, Ndubuisi M, Pincas H, Gerald W, Notterman DA, Barany F, Paty PB (2008) MDM2 gene amplification is correlated to tumor progression but not to the presence of SNP309 or TP53 mutational status in primary colorectal cancers. Mol Cancer Res 6:205–211

    CAS  PubMed  Google Scholar 

  • Freedman DA, Levine AJ (1998) Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol Cell Biol 18:7288–7293

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fridman JS, Lowe SW (2003) Control of apoptosis by p53. Oncogene 22:9030–9040

    CAS  PubMed  Google Scholar 

  • Fuchs SY, Fried VA, Ronai Ze (1998) Stress-activated kinases regulate protein stability. Oncogene 17:1483

    CAS  PubMed  Google Scholar 

  • Graves B, Thompson T, Xia M, Janson C, Lukacs C, Deo D, Di Lello P, Fry D, Garvie C, Huang K-S (2012) Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci USA 109:11788–11793

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gu L, Zhang H, Liu T, Draganov A, Yi S, Wang B, Zhou M (2018) Inhibition of MDM2 by a Rhein-derived compound AQ-101 suppresses Cancer development in SCID mice. Mol Cancer Ther 17:497–507

    CAS  PubMed  Google Scholar 

  • Gu L, Zhang H, Liu T, Zhou S, Du Y, Xiong J, Yi S, Qu CK, Fu H, Zhou M (2016) Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment. Cancer Cell 30:623–636

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77:81–137

    CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    CAS  PubMed  Google Scholar 

  • Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387:296

    CAS  PubMed  Google Scholar 

  • Hou H, Sun D, Zhang X (2019) The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors. Cancer Cell Int 19:216

    PubMed  PubMed Central  Google Scholar 

  • Hu B, Gilkes DM, Chen J (2007) Efficient p53 activation and apoptosis by simultaneous disruption of binding to MDM2 and MDMX. Cancer Res 67:8810–8817

    CAS  PubMed  Google Scholar 

  • Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, Pramanik A, Selivanova G (2004) Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors. Nat Med 10:1321

    CAS  PubMed  Google Scholar 

  • Itahana Y, Ke H, Zhang Y (2009) p53 Oligomerization is essential for its C-terminal lysine acetylation. J Biol Chem 284:5158–5164

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ivanov AA, Khuri FR, Fu H (2013) Targeting protein–protein interactions as an anticancer strategy. Trends Pharm Sci 34:393–400

    CAS  PubMed  Google Scholar 

  • Ju J, Pedersen-Lane J, Maley F, Chu E (1999) Regulation of p53 expression by thymidylate synthase. Proc Natl Acad Sci USA 96:3769–3774

    CAS  PubMed  PubMed Central  Google Scholar 

  • Karni-Schmidt O, Lokshin M, Prives C (2016) The roles of MDM2 and MDMX in cancer. Annu Rev Pathol 11:617–644

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kastan MB, Canman CE, Leonard CJ (1995) P53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev 14:3–15

    CAS  PubMed  Google Scholar 

  • Korsmeyer S, Wei M, Saito M, Weiler S, Oh K, Schlesinger P (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166

    CAS  PubMed  Google Scholar 

  • Krajewski M, Ozdowy P, D’Silva L, Rothweiler U, Holak TA (2005) NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro. Nat Med 11:1135–1136. author reply 1136-1137

    CAS  PubMed  Google Scholar 

  • Kruse J-P, Gu W (2009) Modes of p53 regulation. Cell 137:609–622

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274:948–953

    CAS  PubMed  Google Scholar 

  • Ladds MJ, Laín S (2019) Small molecule activators of the p53 response. J Mol Cell Biol 11:245–254

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lai AC, Crews CM (2017a) Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov 16:101–114

    CAS  PubMed  Google Scholar 

  • Lai AC, Crews CM (2017b) Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov 16:101

    CAS  PubMed  Google Scholar 

  • Lane D, Levine A (2010) p53 Research: the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol 2:a000893

    CAS  PubMed  PubMed Central  Google Scholar 

  • Langenberg M, Schellens J, Lolkema M, Varga A, Demers B, Thomas K, Hsu K, Tuffal G, Goodstal S, Macé S (2019) A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. Br J Cancer 120:286–293

    PubMed  Google Scholar 

  • Lee H, Mok KH, Muhandiram R, Park K-H, Suk J-E, Kim D-H, Chang J, Sung YC, Choi KY, Han K-H (2000) Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J Biol Chem 275:29426–29432

    CAS  PubMed  Google Scholar 

  • Lee J-H, Jin Y, He G, Zeng SX, Wang YV, Wahl GM, Lu H (2012) Hypoxia activates tumor suppressor p53 by inducing ATR-Chk1 kinase cascade-mediated phosphorylation and consequent 14-3-3γ inactivation of MDMX protein. J Biol Chem 287:20898–20903

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lemos A, Leao M, Soares J, Palmeira A, Pinto M, Saraiva L, Sousa ME (2016) Medicinal Chemistry Strategies to Disrupt the p53-MDM2/MDMX Interaction. Med Res Rev 36:789–844

    CAS  PubMed  Google Scholar 

  • Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331

    CAS  PubMed  Google Scholar 

  • Li B, Yang XX, Li L (2017) Research progress in the synthesis and bioactivity of stapled peptide. Acta Pharm Sin 52:685–698

    Google Scholar 

  • Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, Yang C-Y, Wang M, Han X, Wang S (2018) Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J Med Chem 62:448–466

    PubMed  PubMed Central  Google Scholar 

  • Lin J, Chen J, Elenbaas B, Levine AJ (1994) Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev 8:1235–1246

    CAS  PubMed  Google Scholar 

  • Linke K, Mace P, Smith C, Vaux D, Silke J, Day CL (2008) Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ 15:841

    CAS  PubMed  Google Scholar 

  • Linke SP, Clarkin KC, Di Leonardo A, Tsou A, Wahl GM (1996) A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev 10:934–947

    CAS  PubMed  Google Scholar 

  • Linzer DI, Levine AJ (1979) Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52

    CAS  PubMed  Google Scholar 

  • Marine J-C, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G (2006) Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ 13:927–934

    CAS  PubMed  Google Scholar 

  • Meng LH, Kohlhagen G, Liao ZY, Antony S, Sausville E, Pommier Y (2005) DNA-protein cross-links and replication-dependent histone H2AX phosphorylation induced by aminoflavone (NSC 686288), a novel anticancer agent active against human breast cancer cells. Cancer Res 65:5337–5343

    CAS  PubMed  Google Scholar 

  • Meng LH, Kohn KW, Pommier Y (2007) Dose-response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686,288). Oncogene 26:4806–4816

    CAS  PubMed  Google Scholar 

  • Modell AE, Blosser SL, Arora PS (2016) Systematic targeting of protein–protein interactions. Trends Pharm Sci 37:702–713

    CAS  PubMed  Google Scholar 

  • Moll UM, Petrenko O (2003) The MDM2-p53 interaction. Mol Cancer Res 1:1001–1008

    CAS  PubMed  Google Scholar 

  • Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245

    CAS  PubMed  Google Scholar 

  • Montesinos P, Beckermann BM, Catalani O, Esteve J, Gamel K, Konopleva MY, Martinelli G, Monnet A, Papayannidis C, Park A, Recher C, Rodriguez-Veiga R, Rollig C, Vey N, Wei AH, Yoon SS, Fenaux P (2020) MIRROS: a randomized, placebo-controlled, Phase III trial of cytarabine +/- idasanutlin in relapsed or refractory acute myeloid leukemia. Future Oncol 16:807–815

    CAS  PubMed  Google Scholar 

  • Mosner J, Mummenbrauer T, Bauer C, Sczakiel G, Grosse F, Deppert W (1995) Negative feedback regulation of wild‐type p53 biosynthesis. EMBO J 14:4442–4449

    CAS  PubMed  PubMed Central  Google Scholar 

  • Müller S, Berger M, Lehembre F, Seeler J-S, Haupt Y, Dejean A (2000) c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 275:13321–13329

    PubMed  Google Scholar 

  • Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R (2013) The MDM2-p53 pathway revisited. J Biomed Res 27:254–271

    CAS  PubMed  PubMed Central  Google Scholar 

  • Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW (1999) p53/p21 (WAF1/CIP1) expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells. Cancer Lett 136:215–221

    CAS  PubMed  Google Scholar 

  • Neklesa TK, Winkler JD, Crews CM (2017) Targeted protein degradation by PROTACs. Pharm Ther 174:138–144

    CAS  Google Scholar 

  • O’Brate A, Giannakakou P (2003) The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist Updates 6:313–322

    Google Scholar 

  • Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2:a001008

    PubMed  PubMed Central  Google Scholar 

  • Onel K, Cordon-Cardo C (2004) MDM2 and prognosis. Mol Cancer Res 2:1–8

    CAS  PubMed  Google Scholar 

  • Paiva S-L, Crews CM (2019) Targeted protein degradation: elements of PROTAC design. Curr Opin Chem Biol 50:111–119

    CAS  PubMed  PubMed Central  Google Scholar 

  • Palumbo MO, Kavan P, Miller W, Panasci L, Assouline S, Johnson N, Cohen V, Patenaude F, Pollak M, Jagoe RT (2013) Systemic cancer therapy: achievements and challenges that lie ahead. Front Pharm 4:57

    Google Scholar 

  • Pavletich NP, Chambers KA, Pabo CO (1993) The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev 7:2556–2564

    CAS  PubMed  Google Scholar 

  • Phan J, Li Z, Kasprzak A, Li B, Sebti S, Guida W, Schönbrunn E, Chen J (2010) Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J Biol Chem 285:2174–2183

    CAS  PubMed  Google Scholar 

  • Pietsch EC, Leu JI-J, Frank AK, Dumont P, George DL, Murphy ME (2007) The tetramerization domain of p53 is required for efficient BAK oligomerization. Cancer Biol Ther 6:1576–1583

    CAS  PubMed  Google Scholar 

  • Popowicz G, Czarna A, Holak T (2008) Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle 7:2441–2443

    CAS  PubMed  Google Scholar 

  • Popowicz GM, Dömling A, Holak TA (2011) The structure-based design of MDM2/MDMX–p53 inhibitors gets serious. Angew Chem Int Ed Engl 50:2680–2688

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qin JJ, Nag S, Voruganti S, Wang W, Zhang R (2012) Natural product MDM2 inhibitors: anticancer activity and mechanisms of action. Curr Med Chem 19:5705–5725

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rew Y, Sun D, Gonzalez-Lopez De Turiso F, Bartberger MD, Beck HP, Canon J, Chen A, Chow D, Deignan J, Fox BM (2012) Structure-based design of novel inhibitors of the MDM2–p53 interaction. J Med Chem 55:4936–4954

    CAS  PubMed  Google Scholar 

  • Ryan KM, Phillips AC, Vousden KH (2001) Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol 13:332–337

    CAS  PubMed  Google Scholar 

  • Saha MN, Jiang H, Yang Y, Zhu X, Wang X, Schimmer AD, Qiu L, Chang H (2012) Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma. PLoS ONE 7:e30215

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanz G, Singh M, Peuget S, Selivanova G (2019) Inhibition of p53 inhibitors: progress, challenges and perspectives. J Mol Cell Biol 11:586–599

    PubMed  PubMed Central  Google Scholar 

  • Seebacher NA, Stacy AE, Porter GM, Merlot AM (2019) Clinical development of targeted and immune based anti-cancer therapies. J Exp Clin Cancer Res 38:156

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J (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 USA 105:3933–3938

    CAS  PubMed  PubMed Central  Google Scholar 

  • Skalniak L, Kocik J, Polak J, Skalniak A, Rak M, Wolnicka-Glubisz A, Holak TA (2018) Prolonged idasanutlin (RG7388) treatment leads to the generation of p53-mutated cells. Cancers 10:396–412

    CAS  PubMed Central  Google Scholar 

  • Song MS, Song SJ, Kim SY, Oh HJ, Lim DS (2008) The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J 27:1863–1874

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP, Saville MK, Jochemsen AG (2001) Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2:1029–1034

    CAS  PubMed  PubMed Central  Google Scholar 

  • Terzuoli E, Puppo M, Rapisarda A, Uranchimeg B, Cao L, Burger AM, Ziche M, Melillo G (2010) Aminoflavone, a ligand of the aryl hydrocarbon receptor, inhibits HIF-1alpha expression in an AhR-independent fashion. Cancer Res 70:6837–6848

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G (2017a) MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol 10:133

    PubMed  PubMed Central  Google Scholar 

  • Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G (2017b) MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol 10:133

    PubMed  PubMed Central  Google Scholar 

  • Valkov NI, Sullivan DM (2003) Tumor p53 status and response to topoisomerase II inhibitors. Drug Resist Updates 6:27–39

    CAS  Google Scholar 

  • Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848

    CAS  PubMed  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    CAS  PubMed  Google Scholar 

  • Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604

    CAS  PubMed  Google Scholar 

  • Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, Liu J-J, Zhao C, Glenn K, Wen Y (2013) Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett 4:466–469

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wade M, Li Y-C, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13:83

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wade M, Wang YV, Wahl GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 20:299–309

    CAS  PubMed  PubMed Central  Google Scholar 

  • Walensky LD, Bird GH (2014) Hydrocarbon-stapled peptides: principles, practice, and progress. J Med Chem 57:6275–6288

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang B, Wu S, Liu J, Yang K, Xie H, Tang W (2019) Development of selective small molecule MDM2 degraders based on nutlin. Eur J Med Chem 176:476–491

    PubMed  Google Scholar 

  • Wang L, Dai W, Lu L (2014a) Osmotic stress-induced phosphorylation of H2AX by polo-like kinase 3 affects cell cycle progression in human corneal epithelial cells. J Biol Chem 289:29827–29835

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang P, Zhou J (2018) Proteolysis targeting chimera (PROTAC): a paradigm-shifting approach in small molecule drug discovery. Curr Top Med Chem 18:1354–1356

    CAS  PubMed  Google Scholar 

  • Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barrière C, Stuckey JA, Meagher JL, Bai L, Liu L (2014b) SAR405838: an optimized inhibitor of MDM2–p53 interaction that induces complete and durable tumor regression. Cancer Res 74:5855–5865

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barrière C, Stuckey JA, Meagher JL, Bai L, Liu L (2014c) SAR405838: an optimized inhibitor of MDM2–p53 interaction that induces complete and durable tumor regression. Cancer Res 74:5855–5865

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Zhao Y, Bernard D, Aguilar A, Kumar S (2012) Targeting the MDM2-p53 protein-protein interaction for new cancer therapeutics. In: Wendt M (ed.) Protein–protein interactions. Topics in Medicinal Chemistry, vol 8. Springer, Berlin, Heidelberg, p 57–79

  • Wang X, Jiang X (2012) Mdm2 and MdmX partner to regulate p53. FEBS Lett 586:1390–1396

    CAS  PubMed  Google Scholar 

  • Wang Y, Sun H, Xiao Z, Zhang D, Bao X, Wei N (2017) XWL-1-48 exerts antitumor activity via targeting topoisomerase II and enhancing degradation of Mdm2 in human hepatocellular carcinoma. Sci Rep 7:9989

    PubMed  PubMed Central  Google Scholar 

  • Winter A, Higueruelo AP, Marsh M, Sigurdardottir A, Pitt WR, Blundell TL (2012) Biophysical and computational fragment-based approaches to targeting protein–protein interactions: applications in structure-guided drug discovery. Q Rev Biophys 45:383–426

    CAS  PubMed  Google Scholar 

  • World Health Organization (2013) International classification of diseases for oncology (ICD-O), 3rd edn. 1st revision. Geneva

  • Wu L, Maki CG (2005) MDM2: RING finger protein and regulator of p53. In: Iuchi S, Kuldell N (eds) Zinc finger proteins. Molecular Biology Intelligence Unit. Springer, Boston, MA, p 252–260

  • Wurz RP, Cee VJ (2019) Targeted degradation of MDM2 as a new approach to improve the efficacy of MDM2-p53 inhibitors. J Med Chem 62:445–447

    CAS  PubMed  Google Scholar 

  • Yan H, Wu H, Zhang H, Ashton C, Tong C, Wu J, Qian Q, Wang H, Ying Q (2013) DNA damage-induced sustained p53 activation contributes to inflammation-associated hepatocarcinogenesis in rats. Oncogene 32:4565

    CAS  PubMed  Google Scholar 

  • Yang J, Li Y, Aguilar A, Liu Z, Yang CY, Wang S (2019) Simple structural modifications converting a bona fide MDM2 PROTAC degrader into a molecular glue molecule: a cautionary tale in the design of PROTAC degraders. J Med Chem 62:9471–9487

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Sun G, Yang C, Wang B (2011) Novel rhein analogues as potential anticancer agents. ChemMedChem 6:2294–2301

    CAS  PubMed  Google Scholar 

  • Zeke A, Misheva M, Reményi A, Bogoyevitch MA (2016) JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev 80:793–835

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Gu L, Li J, Shah N, He J, Yang L, Hu Q, Zhou M (2010) Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. Cancer Res 70:9895–9904

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Lu H (2009) Signaling to p53: ribosomal proteins find their way. Cancer Cell 16:369–377

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, Shargary S, Bernard D, Li X, Zhao T (2013) A potent small-molecule inhibitor of the MDM2–p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J Med Chem 56:5553–5561

    CAS  PubMed  Google Scholar 

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Acknowledgements

Work in the Wang lab on the subject of MDM2–p53 was partially supported by a grant from the National Institutes of Health (CA180519). We also thank the Georgia Research Alliance for an Eminent Scholar Endowment and GSU for some internal financial support.

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  1. These authors contributed equally: Abiodun Anifowose, Ayodeji A. Agbowuro

Authors and Affiliations

  1. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Petit Science Center, 100 Piedmont Ave, Atlanta, GA, 30303, USA

    Abiodun Anifowose, Ayodeji A. Agbowuro, Xiaoxiao Yang & Binghe Wang

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  1. Abiodun Anifowose
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  2. Ayodeji A. Agbowuro
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  3. Xiaoxiao Yang
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  4. Binghe Wang
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Correspondence to Binghe Wang.

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Dedicated to Professor Robert P. Hanzlik on the occasion of his retirement from the Medicinal Chemistry Department, University of Kansas.

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Anifowose, A., Agbowuro, A.A., Yang, X. et al. Anticancer strategies by upregulating p53 through inhibition of its ubiquitination by MDM2. Med Chem Res 29, 1105–1121 (2020). https://doi.org/10.1007/s00044-020-02574-9

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