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

  • ACS Med Chem Lett. 2024 May 20;15(6):791-797. doi: 10.1021/acsmedchemlett.4c00113.
Simon C C Lucas  1 ,  J Henry Blackwell  1 ,  Ulf Börjesson  2 ,  David Hargreaves  3 ,  Alexander G Milbradt  3 ,  Samiyah Ahmed  4 ,  Mark J Bostock  3 ,  Carine Guerot  5 ,  Andrea Gohlke  3 ,  Olaf Kinzel  6 ,  Michelle L Lamb  7 ,  Nidhal Selmi  8 ,  Christopher J Stubbs  3 ,  Nancy Su  9 ,  Qibin Su  7 ,  Haiou Luo  10 ,  Ting Xiong  10 ,  Xiaoqian Zuo  10 ,  Sana Bazzaz  11 ,  Corey Bienstock  11 ,  Paolo A Centrella  11 ,  Kyle E Denton  11 ,  Diana Gikunju  11 ,  Marie-Aude Guié  11 ,  John P Guilinger  11 ,  Christopher Hupp  11 ,  Anthony D Keefe  11 ,  Takashi Satoh  11 ,  Ying Zhang  11 ,  Emma L Rivers  1
Affiliations
  • 1. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 3. Mechanistic and Structural Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K.
  • 4. Discovery Biology, Discovery Sciences, R&DAstraZeneca, Cambridge CB2 0AA, U.K.
  • 5. Medicinal Chemistry, Oncology, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 6. Medicinal Chemistry, Oncology, R&D, Acerta B.V., a member of the AstraZeneca Group, Oss 5349, The Netherlands.
  • 7. Medicinal Chemistry, Oncology, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 8. Compound Synthesis and Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 9. Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 10. Pharmaron Beijing Co., Ltd., Beijing 100176, P. R. China.
  • 11. X-Chem Inc., Waltham, Massachusetts 02453, United States.
PMID: 38894895 DOI: 10.1021/acsmedchemlett.4c00113
Abstract

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.

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