Optimization of IRAK1/4/pan-FLT3 kinase inhibitors as treatments for acute myeloid leukemia.

FLT3 kinase inhibitors have been advanced to the clinic as targeted treatments for acute myeloid leukemia (AML). These inhibitors can produce promising initial responses, but patients often relapse with treatment-resistant disease. A significant factor contributing to relapse involves adaptive signaling through an alternative pathway mediated by IRAK1 and IRAK4 kinases. Compounds that inhibit IRAK1/4 and FLT3 may thus provide superior efficacy relative to compounds that inhibit FLT3 only. We report the optimization of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization efforts have produced key compound 31, which displays potent inhibition of IRAK1, IRAK4, and FLT3, potent activity in multiple AML tumor cell viability assays, and efficacy superior to that of approved FLT3 inhibitors in multiple mouse xenograft models of AML.