1,4,5-Trisubstituted Imidazole-Based p53-MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological CarriersTwarda-Clapa, A., Krzanik, S., Kubica, K., Guzik, K., Labuzek, B., Neochoritis, C. G., Khoury, K., Kowalska, K., Czub, M., Dubin, G., Dömling, A., Skalniak, L. & Holak, T. A., 25-May-2017, In : Journal of Medicinal Chemistry. 60, 10, p. 4234-4244 11 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||11|
|Journal||Journal of Medicinal Chemistry|
|Publication status||Published - 25-May-2017|
- 1,4,5 trisubstituted imidazole derivative, antineoplastic agent, idasanutlin, imidazole derivative, nutlin 3, protein inhibitor, protein MDM2, protein MDMX, protein p21, protein p53, unclassified drug, article, cancer cell, cancer cell culture, cancer inhibition, cell cycle arrest, controlled study, crystal structure, dimerization, drug conjugation, drug protein binding, drug structure, drug synthesis, HCT 116 cell line, human, in vitro study, SaOS-2 cell line