Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.

Autor: Lucas SCC; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Blackwell JH; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Börjesson U; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden., Hargreaves D; Mechanistic and Structural Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K., Milbradt AG; Mechanistic and Structural Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K., Ahmed S; Discovery Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K., Bostock MJ; Mechanistic and Structural Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K., Guerot C; Medicinal Chemistry, Oncology, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Gohlke A; Mechanistic and Structural Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K., Kinzel O; Medicinal Chemistry, Oncology, R&D, Acerta B.V., a member of the AstraZeneca Group, Oss 5349, The Netherlands., Lamb ML; Medicinal Chemistry, Oncology, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States., Selmi N; Compound Synthesis and Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden., Stubbs CJ; Mechanistic and Structural Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K., Su N; Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States., Su Q; Medicinal Chemistry, Oncology, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States., Luo H; Pharmaron Beijing Co., Ltd., Beijing 100176, P. R. China., Xiong T; Pharmaron Beijing Co., Ltd., Beijing 100176, P. R. China., Zuo X; Pharmaron Beijing Co., Ltd., Beijing 100176, P. R. China., Bazzaz S; X-Chem Inc., Waltham, Massachusetts 02453, United States., Bienstock C; X-Chem Inc., Waltham, Massachusetts 02453, United States., Centrella PA; X-Chem Inc., Waltham, Massachusetts 02453, United States., Denton KE; X-Chem Inc., Waltham, Massachusetts 02453, United States., Gikunju D; X-Chem Inc., Waltham, Massachusetts 02453, United States., Guié MA; X-Chem Inc., Waltham, Massachusetts 02453, United States., Guilinger JP; X-Chem Inc., Waltham, Massachusetts 02453, United States., Hupp C; X-Chem Inc., Waltham, Massachusetts 02453, United States., Keefe AD; X-Chem Inc., Waltham, Massachusetts 02453, United States., Satoh T; X-Chem Inc., Waltham, Massachusetts 02453, United States., Zhang Y; X-Chem Inc., Waltham, Massachusetts 02453, United States., Rivers EL; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 May 20; Vol. 15 (6), pp. 791-797. Date of Electronic Publication: 2024 May 20 (Print Publication: 2024).
DOI: 10.1021/acsmedchemlett.4c00113
Abstrakt: 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.
Competing Interests: The authors declare no competing financial interest.
(© 2024 American Chemical Society.)
Databáze: MEDLINE