Optimization and Chemoproteomic Profiling of a Selective, Covalent Bfl-1-Targeting Cellular Tool
We describe herein the discovery and optimization of a potent and irreversible cellular probe for selective labeling of <b>Bfl-1</b>, a member of the <b>Bcl-2 family</b>. This chemical series demonstrates robust selectivity for Bfl-1 over other related antiapoptotic proteins and exhibits favorable cellular potency as well as promising <i>in vivo</i> pharmacokinetics. Notably, compound <b>25</b> achieves a <i>k</i><sub>inact</sub>/<i>K</i><sub><i>I</i></sub> value of <b>9300 M</b><sup><b>-1</b></sup><b>s</b><sup><b>-1</b></sup> and elicits caspase activation at submicromolar concentrations in cellular assays. To comprehensively profile proteome-wide selectivity, we performed chemoproteomic analyses on compound <b>25</b> 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.
Authors
- Erin L. Braybrooke
- Mark J. Bostock (ORCID: https://orcid.org/0000-0001-6717-5786)
- Olaf Kinzel (ORCID: https://orcid.org/0000-0001-7357-2833)
- Kevin Beaumont (ORCID: https://orcid.org/0000-0001-8721-6450)
- Michael Lainchbury
- Adeline Palisse (ORCID: https://orcid.org/0000-0001-8944-9565)
- Vera van Hoeven (ORCID: https://orcid.org/0000-0003-4134-4072)
- Tony Cheung
- Alexander G. Milbradt
- David Hargreaves (ORCID: https://orcid.org/0000-0003-4441-0039)
- Claudia Sacchetto
- Leonardo J. Leon
- Aarti Kawatkar (ORCID: https://orcid.org/0000-0003-1081-7500)
- Chimed Jansen
- Maaike van Hoek- Emmelot
- Nancy Su
- Rick J.C. Schellekens
- Hua Xu (ORCID: https://orcid.org/0000-0002-1781-6044)
- Andrea Gohlke (ORCID: https://orcid.org/0000-0002-5447-5453)
- Ulf Börjesson
- M.A. Cottee (ORCID: https://orcid.org/0000-0002-3619-3057)
- Giovanni Battocchio
- Lea Kupcova
- Markus Schade
- Yunhua Chen
- Kim van Rijbroek
- Simon C. C. Lucas
- Shen Huang
- Heng Zhao
- Praveen Kumar
- J. Henry Blackwell
Institutions
- Target (United States) (US)
- Abterra Biosciences (United States) (US)
- Pharmaron (United Kingdom) (GB)
- AstraZeneca (Brazil) (BR)
- AstraZeneca (Poland) (PL)
- AstraZeneca (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-12-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02581
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00