Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases.
Henderson SH., Sorrell FJ., Bennett JM., Fedorov O., Hanley MT., Godoi PH., Ruela de Sousa R., Robinson S., Navratilova IH., Elkins JM., Ward SE.
Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.