Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2.

Journal of medicinal chemistry 2021 May 13

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The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.

Citation

Michael J Roy, Amelia Vom, Toru Okamoto, Brian J Smith, Richard W Birkinshaw, Hong Yang, Houda Abdo, Christine A White, David Segal, David C S Huang, Jonathan B Baell, Peter M Colman, Peter E Czabotar, Guillaume Lessene. Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2. Journal of medicinal chemistry. 2021 May 13;64(9):5447-5469