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Publication Abstract from PubMed

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.

Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.,Lucas SCC, Blackwell JH, Borjesson U, Hargreaves D, Milbradt AG, Ahmed S, Bostock MJ, Guerot C, Gohlke A, Kinzel O, Lamb ML, Selmi N, Stubbs CJ, Su N, Su Q, Luo H, Xiong T, Zuo X, Bazzaz S, Bienstock C, Centrella PA, Denton KE, Gikunju D, Guie MA, Guilinger JP, Hupp C, Keefe AD, Satoh T, Zhang Y, Rivers EL ACS Med Chem Lett. 2024 May 20;15(6):791-797. doi: , 10.1021/acsmedchemlett.4c00113. eCollection 2024 Jun 13. PMID:38894895^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.