Peptide directed binding; a novel approach for the discovery of modulators of alpha-helix mediated protein-protein interactions demonstrated with apoptosis regulating Mcl-1
Targeting PPIs with small molecules can be challenging due to large, hydrophobic binding surfaces. Here, we describe a strategy that exploits selective alpha-helical PPIs, transferring these characteristics to small molecules. The proof-of-concept is exemplified 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 ~50% of the small molecules prepared showed an IC50 less than 100 µM and ~25% had IC50 values less than 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 alpha-helical PPI modulators.
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