Novel water-soluble and highly efficient dual type I/II next generation inhibitors of FMS-like tyrosine kinase 3 (FLT3)

Mutations of the FMS-like tyrosine kinase (FLT3) occur in acute myeloid leukemia (AML) and are associated with very poor prognosis. Available FLT3 inhibitors are potent but either show a lack of selectivity regarding other tyrosine kinases or only transient efficacy due to emerging resistance under therapy. Water-soluble derivatives of the tyrosine kinase inhibitor Marbotinib are highly selective dual-type I/II inhibitors of FLT3. The bisarylmethanone-based compound 29 and its carbamate derivative 42 show excellent results in various biological tests. They inhibit FLT3-ITD (internal tandem duplication) as well as therapy-associated FLT3-TKD point mutations. Additionally, good water solubility and consequently biological availability was achieved by attaching amine functions to appropriate scaffold positions, suggested by modeling of inhibitor binding at inactive and active FLT3 states. Subsequent formation of different salts led to very promising results in in vivo studies and improvements compared to midostaurin (1b), Quizartinib (7), Marbotinib 10 and its carbamate 11c.