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Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors.

Miyazaki M, Naito H, Sugimoto Y, Yoshida K, Kawato H, Okayama T, Shimizu H, Miyazaki M, Kitagawa M, Seki T, Fukutake S, Shiose Y, Aonuma M, Soga T
Bioorg Med Chem 21 4319-31 (2013)
Cited: 12 times
EuropePMC logo PMID: 23685175

Abstract

We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.

Reviews - 3w69 mentioned but not cited (5)

  1. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. Zhao Y, Aguilar A, Bernard D, Wang S. J Med Chem 58 1038-1052 (2015)
  2. How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures. Estrada-Ortiz N, Neochoritis CG, Dömling A. ChemMedChem 11 757-772 (2016)
  3. Recent Small-Molecule Inhibitors of the p53-MDM2 Protein-Protein Interaction. Beloglazkina A, Zyk N, Majouga A, Beloglazkina E. Molecules 25 E1211 (2020)
  4. Focusing on shared subpockets - new developments in fragment-based drug discovery. Abdelraheem EM, Camacho CJ, Dömling A. Expert Opin Drug Discov 10 1179-1187 (2015)
  5. Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions. Ershov PV, Mezentsev YV, Ivanov AS. Biomolecules 12 106 (2022)

Articles - 3w69 mentioned but not cited (1)

  1. An Integrative Analysis Reveals a Central Role of P53 Activation via MDM2 in Zika Virus Infection Induced Cell Death. Teng Y, Liu S, Guo X, Liu S, Jin Y, He T, Bi D, Zhang P, Lin B, An X, Feng D, Mi Z, Tong Y. Front Cell Infect Microbiol 7 327 (2017)


Reviews citing this publication (1)

  1. Targeting MDM2-p53 interaction for cancer therapy: are we there yet? Nag S, Zhang X, Srivenugopal KS, Wang MH, Wang W, Zhang R. Curr Med Chem 21 553-574 (2014)

Articles citing this publication (5)

  1. Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma. Chen L, Zhao Y, Halliday GC, Berry P, Rousseau RF, Middleton SA, Nichols GL, Del Bello F, Piergentili A, Newell DR, Lunec J, Tweddle DA. Br J Cancer 111 716-725 (2014)
  2. Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor. Miyazaki M, Uoto K, Sugimoto Y, Naito H, Yoshida K, Okayama T, Kawato H, Miyazaki M, Kitagawa M, Seki T, Fukutake S, Aonuma M, Soga T. Bioorg Med Chem 23 2360-2367 (2015)
  3. Inhibition of nutlin-resistant HDM2 mutants by stapled peptides. Wei SJ, Joseph T, Chee S, Li L, Yurlova L, Zolghadr K, Brown C, Lane D, Verma C, Ghadessy F. PLoS One 8 e81068 (2013)
  4. Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction. Vaupel A, Bold G, De Pover A, Stachyra-Valat T, Lisztwan JH, Kallen J, Masuya K, Furet P. Bioorg Med Chem Lett 24 2110-2114 (2014)
  5. Identification of new inhibitors of Mdm2-p53 interaction via pharmacophore and structure-based virtual screening. Atatreh N, Ghattas MA, Bardaweel SK, Rawashdeh SA, Sorkhy MA. Drug Des Devel Ther 12 3741-3752 (2018)


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