Adeline Palisse, Tony Cheung, Aileen Blokhuis, Thomas Cogswell, Bruna S. Martins, Rick Riemens, Rick Schellekens, Giovanni Battocchio, Chimed Jansen, Matthew A. Cottee, Kimberly Ornell, Claudia Sacchetto, Leonardo Leon, Maaike van Hoek- Emmelot, Mark Bostock, Brooke Leann Brauer, Kevin Beaumont, Simon C. C. Lucas, Samiyah Ahmed, J. Henry Blackwell, Ulf Börjesson, Andrea Gohlke, Iva Monique T. Gramatikov, David Hargreaves, Vera van Hoeven, Vasudev Kantae, Lea Kupcova, Alexander G. Milbradt, Uthpala Seneviratne, Nancy Su, John Vales, Haiyun Wang, Michael J. White, and Olaf Kinzel
Journal of Medicinal Chemistry 2024
DOI: 10.1021/acs.jmedchem.4c01995
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 in vivo tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound 6.22 This work reports the structure-based optimization of compound 6 into a series of BFL1 inhibitors selective over the other BCL2 family members, with low nanomolar cellular activity when combined with AZD5991, exemplified by compound 20. Compound 20 demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the in vivo 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 20 stabilized the protein, extending the half-life to 10.8 h.
