Structure-Based\nDiscovery of a Series of Covalent,\nOrally Bioavailable, and Selective BFL1 Inhibitors

BFL1, a member of the antiapoptotic BCL2 family, has\nbeen relatively\nunderstudied compared to its counterparts despite evidence of its\noverexpression in various hematological malignancies. Across two articles,\nwe describe the development of BFL1 <i>in vivo</i> tools.\nThe first article describes the hit identification from a covalent\nfragment library and the subsequent evolution from the hit to compound <b>6</b>.<sup>22</sup> This work reports the structure-based optimization\nof compound <b>6</b> into a series of BFL1 inhibitors selective\nover 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\nin SUDHL1 and OCILY10 cell lines and in the <i>in vivo</i> study, BFL1 stabilization and cleaved caspase 3 activation were\nobserved in a dose-dependent manner. In addition, the enzymatic turnover\nstudies with the BFL1 protein showed that compound <b>20</b> stabilized the protein, extending the half-life to 10.8 h.