Beekman, Andrew Michael, O'Connell, Maria Anne and Howell, Lesley Ann (2017) Peptide-directed binding for the discovery of modulators of α-helix-mediated protein-protein interactions: Proof-of-concept studies with the apoptosis regulator Mcl-1. Angewandte Chemie International Edition, 56 (35). 10446–10450. ISSN 1433-7851

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Abstract

Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective α-helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl-1, commonly exploited by cancers to avoid cell death. Peptide-directed binding uses few synthetic transformations, requires the production of a small number of compounds, and generates a high percentage of hits. In this example, about 50 % of the small molecules prepared showed an IC50 value of less than 100 μm, and approximately 25 % had IC50 values below 1 μm to Mcl-1. Compounds show selectivity for Mcl-1 over other anti-apoptotic proteins, possess cytotoxicity to cancer cell lines, and induce hallmarks of apoptosis. This approach represents a novel and economic process for the rapid discovery of new α-helical PPI modulators.

Item Type:	Article
Uncontrolled Keywords:	apoptosis,drug discovery,medicinal chemistry,protein–protein interactions,solid-phase synthesis
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Pure Connector
Date Deposited:	06 Jul 2017 05:06
Last Modified:	26 Aug 2020 23:49
URI:	https://ueaeprints.uea.ac.uk/id/eprint/64037
DOI:	10.1002/anie.201705008

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