Discovery of selective, metabolically stable pyrazole-based FLT3 inhibitors for the treatment of acute myeloid leukemia.

Abstract

Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia in adults, representing a substantial medical need, as the standard of care has not changed for the past two decades, and the long-term outcome remains dismal for a large fraction of patients. Approximately 30% of AMLs carry activating mutations of the FLT3 kinase. Unfortunately, single-agent FLT3 inhibitor therapy has met limited clinical efficacy, underscoring a strong rationale for the development of more selective and more potent inhibitors. Here we present the design, synthesis and biological evaluation of a series of biphenyl substituted pyrazoyl-ureas, an underexplored scaffold in medicinal chemistry, as novel FLT3 inhibitors with a putative type II binding mode. Optimized compounds show nanomolar activity against isolated FLT3 (230 nM for compound 10q) and on FLT3-driven cell lines (280 nM and 18 nM for compound 10q against MV4.11 and MOLM-14 cells respectively), with no toxicity against control cell lines, limited metabolism in human microsomes and a reliable SAR; furthermore, profiling of compound 10q against a panel of kinases highlights c-Kit as the only other hit. Overall, we show that the series has a narrow selectivity profile and metabolic stability, and the mode of action of the inhibitors through FLT3 is confirmed by strong suppression of FLT3 and STAT5 phosphorylation.