{Reference Type}: Journal Article
{Title}: Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1.
{Author}: Lou J;Zhou Q;Lyu X;Cen X;Liu C;Yan Z;Li Y;Tang H;Liu Q;Ding J;Lu Y;Huang H;Xie H;Zhao Y;
{Journal}: J Med Chem
{Volume}: 67
{Issue}: 13
{Year}: 2024 Jul 11
{Factor}: 8.039
{DOI}: 10.1021/acs.jmedchem.4c00291
{Abstract}: 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.