Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL‑1

Clinical and biological studies have
shown that overexpression
of BFL-1 is one contributing factor to venetoclax resistance. The
resistance might be overcome by a potent BFL-1 inhibitor, but such
an inhibitor is rare. In this study, we show that 56, featuring an acrylamide moiety, inhibited the BFL-1/BID interaction
with a Ki value of 105 nM. More interestingly, 56 formed an irreversible conjugation adduct at the C55 residue
of BFL-1. 56 was a selective BFL-1 inhibitor, and its
MCL-1 binding affinity was 10-fold weaker, while it did not bind BCL-2
and BCL-xL. Mechanistic studies showed that 56 overcame
venetoclax resistance in isogenic AML cell lines MOLM-13-OE and MV4-11-OE,
which both overexpressed BFL-1. More importantly, 56 and
venetoclax combination promoted stronger apoptosis induction than
either single agent. Collectively, our data show that 56 overcame resistance to venetoclax in AML cells overexpressing BFL-1.
These attributes make 56 a promising candidate for future
optimization.