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Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction

Vaupel, Andrea and Bold, Guido and Valat, Therese-Marie and Kallen, Joerg and Masuya, Keiichi and Furet, Pascal and de Pover, Alain and Hergovich-Lisztwan, Joanna (2014) Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction. Bioorganic and Medicinal Chemistry Letters, 24 (9). pp. 2110-2114. ISSN 0960894X

Abstract

Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency achieved in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line.

Item Type: Article
Keywords: p53-MDM2 inhibitors, structure-based design, medicinal chemistry
Date Deposited: 18 May 2016 23:45
Last Modified: 04 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/20571

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