Structure-guided development of potent Benzoylurea Inhibitors of BCL-X(L) and BCL-2
Publication Year 2021-04-27, Volume 64, Issue #9, Page 5447-5469
Journal Title
Journal of Medicinal Chemistry
The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-X(L), 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-X(L), new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-X(L)/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-X(L). This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-X(L). Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-X(L) and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC(50))) and displaying mechanism-based killing in cells engineered to depend on BCL-X(L) for survival.
WEHI Research Division(s)
Chemical Biology; Blood Cells And Blood Cancer; Personalised Oncology; Structural Biology
PubMed ID
Rights Notice
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Creation Date: 2021-05-11 04:12:14
Last Modified: 2021-05-17 11:22:57
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