Peptide-Directed Binding for the Discovery of Modulators of ?-Helix-Mediated Protein–Protein Interactions: Proof-of-Concept Studies with the Apoptosis Regulator Mcl-1
Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective ?-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 ?m, and approximately 25 % had IC50 values below 1 ?m 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 ?-helical PPI modulators.Selective ?-helical protein–protein interactions were exploited to develop small-molecule inhibitors of these interactions. Proof-of-concept studies were conducted with the apoptosis regulator Mcl-1, and compounds that show selectivity for Mcl-1 over other anti-apoptotic proteins, are cytotoxic to cancer cell lines, and induce hallmarks of apoptosis were thus identified.
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