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1,4,5-Trisubstituted Imidazole-Based p53-MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers.

Twarda-Clapa A, Krzanik S, Kubica K, Guzik K, Labuzek B, Neochoritis CG, Khoury K, Kowalska K, Czub M, Dubin G, Dömling A, Skalniak L, Holak TA
J Med Chem 60 4234-4244 (2017)
Cited: 11 times
EuropePMC logo PMID: 28482147

Abstract

The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.

Reviews citing this publication (3)

  1. Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Fang Y, Liao G, Yu B. Acta Pharm Sin B 10 1253-1278 (2020)
  2. The long and the short of it: the MDM4 tail so far. Haupt S, Mejía-Hernández JO, Vijayakumaran R, Keam SP, Haupt Y. J Mol Cell Biol 11 231-244 (2019)
  3. Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials. Zhu H, Gao H, Ji Y, Zhou Q, Du Z, Tian L, Jiang Y, Yao K, Zhou Z. J Hematol Oncol 15 91 (2022)

Articles citing this publication (8)

  1. Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma. Wang B, Peng F, Huang W, Zhou J, Zhang N, Sheng J, Haruehanroengra P, He G, Han B. Acta Pharm Sin B 10 1492-1510 (2020)
  2. Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents. Lemos A, Gomes AS, Loureiro JB, Brandão P, Palmeira A, Pinto MMM, Saraiva L, Sousa ME. Molecules 24 E1975 (2019)
  3. Artificial Macrocycles. Abdelraheem EMM, Shaabani S, Dömling A. Synlett 29 1136-1151 (2018)
  4. Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction. Neochoritis CG, Atmaj J, Twarda-Clapa A, Surmiak E, Skalniak L, Köhler LM, Muszak D, Kurpiewska K, Kalinowska-Tłuścik J, Beck B, Holak TA, Dömling A. Eur J Med Chem 182 111588 (2019)
  5. Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration. Chen J, Wang J, Pang L, Zhu W. Chem Biol Drug Des 92 1763-1777 (2018)
  6. The base-free van Leusen reaction of cyclic imines on water: synthesis of N-fused imidazo 6,11-dihydro β-carboline derivatives. Satyam K, Murugesh V, Suresh S. Org Biomol Chem 17 5234-5238 (2019)
  7. Synthesis and Biological Evaluation of Novel Synthetic Indolone Derivatives as Anti-Tumor Agents Targeting p53-MDM2 and p53-MDMX. Wang Y, Ji B, Cheng Z, Zhang L, Cheng Y, Li Y, Ren J, Liu W, Ma Y. Molecules 27 3721 (2022)
  8. Unusual rearrangement of imidazo[1,5-a]imidazoles and imidazo[1,2-b]pyrazoles into imidazo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines. Gambouz K, Driowya M, Loubidi M, Tber Z, Allouchi H, El Kazzouli S, Akssira M, Guillaumet G. RSC Adv 9 29051-29055 (2019)


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