Structure-Based Discovery of a Series of Covalent, Orally Bioavailable, and Selective BFL1 Inhibitors
BFL1, a member of the antiapoptotic BCL2 family, has been relatively understudied compared to its counterparts despite evidence of its overexpression in various hematological malignancies. Across two articles, we describe the development of BFL1 <i>in vivo</i> tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound <b>6</b>.<sup>22</sup> This work reports the structure-based optimization of compound <b>6</b> into a series of BFL1 inhibitors selective over the other BCL2 family members, with low <i>nanomolar</i> cellular activity when combined with AZD5991, exemplified by compound <b>20</b>. Compound <b>20</b> demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the <i>in vivo</i> study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound <b>20</b> stabilized the protein, extending the half-life to 10.8 h.
Authors
- Bruna S. Martins (ORCID: https://orcid.org/0000-0001-9143-4434)
- Mark J. Bostock (ORCID: https://orcid.org/0000-0001-6717-5786)
- M. J. D. White (ORCID: https://orcid.org/0000-0001-9472-7806)
- Olaf Kinzel (ORCID: https://orcid.org/0000-0001-7357-2833)
- Thomas J. Cogswell
- Kevin Beaumont (ORCID: https://orcid.org/0000-0001-8721-6450)
- J. Henry Blackwell (ORCID: https://orcid.org/0000-0003-2003-6660)
- Vasudev Kantae (ORCID: https://orcid.org/0000-0001-8541-0882)
- 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
- Chimed Jansen
- Iva Monique T. Gramatikov (ORCID: https://orcid.org/0000-0001-5789-7961)
- Maaike van Hoek- Emmelot
- Nancy Su
- Uthpala Seneviratne
- Brooke L. Brauer (ORCID: https://orcid.org/0009-0007-6855-5175)
- Rick Riemens
- 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
- Haiyun Wang (ORCID: https://orcid.org/0000-0001-8364-8328)
- Samiyah Ahmed
- Simon C. C. Lucas (ORCID: https://orcid.org/0000-0002-9172-8739)
- Lea Kupcova
- John Vales
- Anna M. Blokhuis
- Kimberly J. Ornell
- R.C.A. Schellekens
Institutions
- AstraZeneca (United Kingdom) (GB)
- Discovery Centre (CA)
- Bioscience Research (US)
- Abterra Biosciences (United States) (US)
- AstraZeneca (Netherlands) (NL)
- AstraZeneca (Brazil) (BR)
- AstraZeneca (Poland) (PL)
- AstraZeneca (Sweden) (SE)
- Institute of Medicinal Plant Development (CN)
- AstraZeneca (United States) (US)
- AstraZeneca (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01995
- Citations
- 3
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.70