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

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

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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