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

Authors

• SB Hoyt
• CJ Finocchio
• E Croll
• GJ Tawa
• H Li
• L Ma
• K Li
• L Liu
• R Li
• X Zhang
• K Wilson
• X Xu
• P Shah
• J Williams
• LC Bolanos
• G Gracia-Maldonado
• A Kolt
• C Robinson
• J Free
• E Edmondson
• S Diflippantonio
• JS Rosenbaum
• DT Starczynowski
• CJ Thomas

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cell cancer with few good treatment options. FLT3 kinase inhibitors have been advanced to the clinic as targeted treatments for AML. When used alone or in combination with other therapies, FLT3 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 discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced a benchmark compound (1) that displays potent and selective inhibition of IRAK1, IRAK4, FLT3 and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, compound 1 produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.

Scientific Focus Area: Chemical Biology

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