Structure-guided development of potent Benzoylurea Inhibitors of BCL-X(L) and BCL-2

Roy, MJ; Vom, A; Okamoto, T; Smith, BJ; Birkinshaw, RW; Yang, H; Abdo, H; White, CA; Segal, D; Huang, DCS; Baell, JB; Colman, PM; Czabotar, PE; Lessene, G

Author(s): Roy, MJ; Vom, A; Okamoto, T; Smith, BJ; Birkinshaw, RW; Yang, H; Abdo, H; White, CA; Segal, D; Huang, DCS; Baell, JB; Colman, PM; Czabotar, PE; Lessene, G;
Details: Publication Year 2021-04-27,Volume 64,Issue #9,Page 5447-5469
Journal Title: Journal of Medicinal Chemistry
Abstract: 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.
Publisher: ACS
Research Division(s): Chemical Biology; Blood Cells And Blood Cancer; Personalised Oncology; Structural Biology
PubMed ID: 33904752
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.0c01771
NHMRC Grants: NHMRC/257502, NHMRC/461221, NHMRC/1016701, NHMRC/305536, NHMRC/1025138,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-05-11 04:12:14

Last Modified: 2021-05-17 11:22:57