Inhibition of Bfl-1 with N-aryl maleimides |
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Authors: | Cashman John R MacDonald Mary Ghirmai Senait Okolotowicz Karl J Sergienko Eduard Brown Brock Garcia Xochella Zhai Dayong Dahl Russell Reed John C |
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Affiliation: | Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, United States. JCashman@hbri.org |
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Abstract: | 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 14 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. |
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