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 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.