9s6m
Structure of BFL1 in complex with a covalent inhibitor, alternative series, cmpd25
Structural highlights
FunctionB2LA1_HUMAN Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). Publication Abstract from PubMedWe describe herein the discovery and optimization of a potent and irreversible cellular probe for selective labeling of Bfl-1, a member of the Bcl-2 family. This chemical series demonstrates robust selectivity for Bfl-1 over other related antiapoptotic proteins and exhibits favorable cellular potency as well as promising in vivo pharmacokinetics. Notably, compound 25 achieves a k(inact)/K(I) value of 9300 M(-1)s(-1) and elicits caspase activation at submicromolar concentrations in cellular assays. To comprehensively profile proteome-wide selectivity, we performed chemoproteomic analyses on compound 25 alongside our previously reported Bfl-1 inhibitors. This enabled critical insights into potential off-target interactions and facilitated direct comparison of off-target profiles among distinct chemotypes targeting Bfl-1. Optimization and Chemoproteomic Profiling of a Selective, Covalent Bfl-1-Targeting Cellular Tool.,Blackwell JH, Lucas SCC, Battocchio G, Borjesson U, Bostock MJ, Braybrooke EL, Cheung T, Cottee MA, Beaumont KC, Gohlke A, Hargreaves D, van Hoek-Emmelot M, van Hoeven V, Jansen C, Kawatkar A, Kinzel O, Kumar P, Kupcova L, Lainchbury MD, Leon L, Milbradt AG, Palisse A, Schade M, van Rijbroek K, Sacchetto C, Schellekens R, Su N, Xu H, Zhao H, Chen Y, Huang S J Med Chem. 2025 Dec 23. doi: 10.1021/acs.jmedchem.5c02581. PMID:41432228[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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