2. Academic Validation
  3. Optimization and Chemoproteomic Profiling of a Selective, Covalent Bfl-1-Targeting Cellular Tool

Optimization and Chemoproteomic Profiling of a Selective, Covalent Bfl-1-Targeting Cellular Tool

  • J Med Chem. 2026 Jan 22;69(2):1218-1246. doi: 10.1021/acs.jmedchem.5c02581.
J Henry Blackwell 1,  Simon C C Lucas 2,  Giovanni Battocchio 3,  Ulf Börjesson 4,  Mark J Bostock 5,  Erin L Braybrooke 1,  Tony Cheung 6,  Matthew A Cottee 5,  Kevin C Beaumont 1,  Andrea Gohlke 5,  David Hargreaves 5,  Maaike van Hoek-Emmelot 7,  Vera van Hoeven 7,  Chimed Jansen 3,  Aarti Kawatkar 8,  Olaf Kinzel 3,  Praveen Kumar 8,  Lea Kupcova 5,  Michael D Lainchbury 2,  Leonardo Leon 6,  Alexander G Milbradt 5,  Adeline Palisse 3,  Markus Schade 1,  Kim van Rijbroek 3,  Claudia Sacchetto 7,  Rick Schellekens 3,  Nancy Su 9,  Hua Xu 8,  Heng Zhao 8,  Yunhua Chen 10,  Shen Huang 10
Affiliations

Affiliations

  • 1 Chemistry and DMPK, Oncology Targeted Discovery, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 3 Chemistry, Oncology Targeted Discovery, R&D, Acerta B. V. a Member of the Astrazeneca Group, Oss 5349, The Netherlands.
  • 4 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 5 Protein Science, Structure and Biophysics, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 6 Bioscience, Oncology Targeted Discovery, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 7 Bioscience, Oncology Targeted Discovery, R&D, Acerta B. V. a Member of the Astrazeneca Group, Oss 5349, The Netherlands.
  • 8 Chemical Biology and Proteomics, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 9 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 10 Pharmaron Beijing Co., Ltd., No.6, Taihe Road, BDA, Beijing 100176, P.R.china.
PMID: 41432228 DOI: 10.1021/acs.jmedchem.5c02581
Abstract

We describe herein the discovery and optimization of a potent and irreversible cellular probe for selective labeling of Bfl-1, a member of the Bcl-2 Family. This chemical series demonstrates robust selectivity for Bfl-1 over Other related antiapoptotic proteins and exhibits favorable cellular potency as well as promising in vivo pharmacokinetics. Notably, compound 25 achieves a kinact/KI value of 9300 M-1s-1 and elicits Caspase activation at submicromolar concentrations in cellular assays. To comprehensively profile proteome-wide selectivity, we performed chemoproteomic analyses on compound 25 alongside our previously reported Bfl-1 inhibitors. This enabled critical insights into potential off-target interactions and facilitated direct comparison of off-target profiles among distinct chemotypes targeting Bfl-1.

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