Publication Abstract from PubMed
We 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.
