Inhibition of Bfl-1 with N-Aryl Maleimides

摘要

High throughput screening of 66,000 compounds using competitive binding of peptides comprising the BH3 domain to anti-apoptotic Bfl-1 led to the identification of fourteen validated “hits” as inhibitors of Bfl-1. N-Aryl maleimide >1 was among the validated “hits”. A chemical library encompassing over 280 analogs of >1 was prepared following a two-step synthesis. Structure-activity studies for inhibition of Bfl-1 by analogs of N-aryl maleimide >1 revealed a preference for electron-withdrawing substituents in the N-aryl ring and hydrophilic amines appended to the maleimide core. Inhibitors of Bfl-1 are potential development candidates for anti-cancer therapeutics.