Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations.

摘要: Numerous FLT3 inhibitors have been explored as a viable therapy for the treatment of acute myeloid leukemia (AML). However, clinical data underwhelming due to incomplete inhibition or emergence resistant mutations treated with these older agents. We previously developed series 3-phenyl-1H-5-pyrazolylamine derivatives highly potent and selective good in vivo efficacy using an intravenous (IV) route. poor bioavailability pyrazole compounds limits development promising antileukemic use. Herein, we describe novel class 5-phenyl-thiazol-2-ylamine that are multi-targeted inhibitors. From this compounds, compound 7h was very against AML cell lines exhibited excellent oral in xenograft models. In addition, further studies demonstrated in vitro activities clinically relevant AC220 (3)-resistant kinase domain mutants FLT3-ITD.