Synergistic Activity of the MCL-1 Inhibitor S63845 with Midostaurin in Preclinical Human Models of FLT3-ITD Mutated Acute Myeloid Leukemia (AML)

S63845 is a BH3-mimetic inhibitor of anti-apoptotic myeloid cell leukemia 1 (Mcl-1) protein, which kills Mcl-1-dependent cancer cells by activating BAX/BAK-dependent mitochondrial apoptotic pathway. Selective upregulation of Mcl-1 is characteristic of acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3-internal tandem duplications (FLT3-ITD). Increased Mcl-1 expression results from abnormal FLT3 signaling and is essential mediator of drug resistance in this subtype of AML.