Searching for novel MDM2/MDMX dual inhibitors through a drug repurposing approach

References

• Stiewe T. The p53 family in differentiation and tumorigenesis. Nat Rev Cancer. 2007;7(3):165–168.
   PubMed Web of Science ®Google Scholar
• Toledo F, Wahl GM. Regulating the P53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6(12):909–923.
   PubMed Web of Science ®Google Scholar
• Vousden KH, Lu X. Live or let die: the cell’s response to P53. Nat Rev Cancer. 2002;2(8):594–604.
   PubMed Web of Science ®Google Scholar
• Marei HE, Althani A, Afifi N, Hasan A, Caceci T, Pozzoli G, Morrione A, Giordano A, Cenciarelli C. P53 signaling in cancer progression and therapy. Cancer Cell Int. 2021;21(1):703.
   PubMed Web of Science ®Google Scholar
• Wade M, Li Y-C, Wahl GM. MDM2, MDMX and P53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13(2):83–96.
   PubMed Web of Science ®Google Scholar
• Manfredi JJ. Mdm2 and MdmX: partners in P53 destruction. Cancer Res. 2021;81(7):1633–1634.
   PubMed Web of Science ®Google Scholar
• Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, Canon J, Chen A, Chen X, Chow D, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2–P53 inhibitor in clinical development. J Med Chem. 2014;57(4):1454–1472.
   PubMed Web of Science ®Google Scholar
• Si D, Luo H, Zhang X, Yang K, Wen H, Li W, Liu J. Design, synthesis and biological evaluation of novel pyrrolidone-based derivatives as potent P53-MDM2 inhibitors. Bioorg Chem. 2021;115:105268.
   PubMed Web of Science ®Google Scholar
• Luo H, Si D, Sun X, Wang M, Yang Y, Wang B, Wen H, Li W, Liu J. Structure-based discovery of novel α-aminoketone derivatives as dual P53-MDM2/MDMX inhibitors for the treatment of cancer. Eur J Med Chem. 2023;252:115282.
   PubMed Web of Science ®Google Scholar
• Carvajal LA, Neriah DB, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, Narayanagari S-R, Wheat JC, Todorova TI, Mitchell K, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med. 2018;10(436).
   PubMed Web of Science ®Google Scholar
• Giustiniano M, Daniele S, Pelliccia S, La Pietra V, Pietrobono D, Brancaccio D, Cosconati S, Messere A, Giuntini S, Cerofolini L, et al. Computer-aided identification and lead optimization of dual murine double minute 2 and 4 binders: structure–activity relationship studies and pharmacological activity. J Med Chem. 2017;60(19):8115–8130.
   PubMed Web of Science ®Google Scholar
• Zhang S, Yan Z, Li Y, Gong Y, Lyu X, Lou J, Zhang D, Meng X, Zhao Y. Structure-based discovery of MDM2/4 dual inhibitors that exert antitumor activities against MDM4-overexpressing cancer cells. J Med Chem. 2022;65(8):6207–6230.
   PubMed Web of Science ®Google Scholar
• Graves B, Thompson T, Xia M, Janson C, Lukacs C, Deo D, Di Lello P, Fry D, Garvie C, Huang K-S, et al. Activation of the P53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci U S A. 2012;109(29):11788–11793.
   PubMed Web of Science ®Google Scholar
• Guerlavais V, Sawyer TK, Carvajal L, Chang YS, Graves B, Ren J-G, Sutton D, Olson KA, Packman K, Darlak K, et al. Discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide in clinical development. J Med Chem. 2023;66(14):9401–9417.
   PubMed Web of Science ®Google Scholar
• Saleh MN, Patel MR, Bauer TM, Goel S, Falchook GS, Shapiro GI, Chung KY, Infante JR, Conry RM, Rabinowits G, et al. Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53. Clin Cancer Res. 2021;27(19):5236–5247.
   PubMed Web of Science ®Google Scholar
• Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41–58.
   PubMed Web of Science ®Google Scholar
• Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68(12):4774–4782.
   PubMed Web of Science ®Google Scholar
• Roth GJ, Binder R, Colbatzky F, Dallinger C, Schlenker-Herceg R, Hilberg F, Wollin S-L, Kaiser R. Nintedanib: from discovery to the clinic. J Med Chem. 2015;58(3):1053–1063.
   PubMed Web of Science ®Google Scholar
• Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP. Structure of the MDM2 oncoprotein bound to the P53 tumor suppressor transactivation domain. Science. 1996;274(5289):948–953.
   PubMed Web of Science ®Google Scholar
• Popowicz G, Czarna A, Holak T. Structure of the human Mdmx protein bound to the P53 tumor suppressor transactivation domain. Cell Cycle. 2008;7(15):2441–2443.
   PubMed Web of Science ®Google Scholar
• Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, Perren T, Gore M, Persic M, et al. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol. 2011;29(28):3798–3804.
   PubMed Web of Science ®Google Scholar
• Cheng A-L, Yen C-J, Kim T-Y, Feng Y-H, Chao Y, Lin D-Y, Loembe A-B, Hocke J, Choi C, Ryoo B-Y. Efficacy and safety of nintedanib versus sorafenib in asian patients with advanced hepatocellular carcinoma (HCC): a randomized phase II trial. JCO. 2015;33(3_suppl):339–339.
   Web of Science ®Google Scholar
• Eisen T, Shparyk Y, Macleod N, Jones R, Wallenstein G, Temple G, Khder Y, Dallinger C, Studeny M, Loembe A-B, et al. Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study. Invest New Drugs. 2013;31(5):1283–1293.
   PubMed Web of Science ®Google Scholar
• Kutzner C, Kniep C, Cherian A, Nordstrom L, Grubmüller H, de Groot BL, Gapsys V. GROMACS in the cloud: a global supercomputer to speed up alchemical drug design. J Chem Inf Model. 2022;62(7):1691–1711.
   PubMed Web of Science ®Google Scholar
• Wang E, Sun H, Wang J, Wang Z, Liu H, Zhang JZH, Hou T. end-point binding free energy calculation with MM/PBSA and MM/GBSA: strategies and applications in drug design. Chem Rev. 2019;119(16):9478–9508.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Aguilar A, Bernard D, Wang S. Small-molecule inhibitors of the MDM2–P53 protein–protein interaction (MDM2 inhibitors) in clinical trials for cancer treatment. J Med Chem. 2015;58(3):1038–1052.
   PubMed Web of Science ®Google Scholar
• Matthews HK, Bertoli C, De Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74–88.
   PubMed Web of Science ®Google Scholar
• Do P-C, Lee EH, Le L. Steered molecular dynamics simulation in rational drug design. J Chem Inf Model. 2018;58(8):1473–1482.
   PubMed Web of Science ®Google Scholar
• Wang E, Fu W, Jiang D, Sun H, Wang J, Zhang X, Weng G, Liu H, Tao P, Hou T. VAD-MM/GBSA: a variable atomic dielectric MM/GBSA model for improved accuracy in protein–ligand binding free energy calculations. J Chem Inf Model. 2021;61(6):2844–2856.
   PubMed Web of Science ®Google Scholar