Structure-Based Optimization of a Series of Covalent, Cell Active Bfl‑1 Inhibitors

Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 repre...

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Published in:	Journal of medicinal chemistry Vol. 67; no. 18; pp. 16455 - 16479
Main Authors:	Lucas, Simon C. C., Blackwell, J. Henry, Börjesson, Ulf, Hargreaves, David, Milbradt, Alexander G., Bostock, Mark J., Ahmed, Samiyah, Beaumont, Kevin, Cheung, Tony, Demanze, Sylvain, Gohlke, Andrea, Guerot, Carine, Haider, Afreen, Kantae, Vasudev, Kauffman, Gregory W., Kinzel, Olaf, Kupcova, Lea, Lainchbury, Michael D., Lamb, Michelle L., Leon, Leonardo, Palisse, Adeline, Sacchetto, Claudia, Storer, R. Ian, Su, Nancy, Thomson, Clare, Vales, John, Chen, Yunhua, Hu, Xiaolong
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 26-09-2024
Subjects:	Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Line, Tumor Crystallography, X-Ray Humans Mice Minor Histocompatibility Antigens Models, Molecular Molecular Structure Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - metabolism Structure-Activity Relationship
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Summary:	Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound (R,R,S)-26 has a k inact /K I of 4600 M–1 s–1, shows <1 μM caspase activation in a cellular assay and cellular target engagement, and has good physicochemical properties and a promising in vivo profile.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804 1520-4804
DOI:	10.1021/acs.jmedchem.4c01288