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
  • 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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