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

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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.
Original languageEnglish
Pages (from-to)10446–10450
Number of pages5
JournalAngewandte Chemie-International Edition
Issue number35
Early online date25 Jul 2017
Publication statusPublished - 21 Aug 2017


  • apoptosis
  • drug discovery
  • medicinal chemistry
  • protein–protein interactions
  • solid-phase synthesis

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