Discovery and optimization of (2-naphthylthio)acetic acid derivative as selective Bfl-1 inhibitor

Bcl-2 anti-apoptotic protein family suppresses cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Bfl-1 is a relatively understudied member of this family, though it has been implicated in the pathogenesis and chemoresistance of a variety of human cancers. Reported small molecular Bfl-1 inhibitors encountered the issue of either lack in potency or poor selectivity against its most homologous member Mcl-1. In order to tackle this issue, compound library was screened and a hit compound UMI-77 was identified. We modified its chemical structure to remove the characteristic of PAINS (pan-assay interference compounds), demonstrated the real binding affinity and achieved selectivity against Mcl-1 under the guidance of computational modeling. After optimization 15 was obtained as leading compound to block Bfl-1/Bim interaction in vitro with more than 10-fold selectivity over Mcl-1. We believe 15 is of great value for the exploration of Bfl-1 biological function and its potential as therapeutic target.

(2-naphthylthio)acetic acid derivative; Bcl-2 anti-apoptotic protein; Bfl-1 inhibitor; Selectivity; pan-assay interference compounds (PAINS).