Imidazo[1,2-B]Pyridazines as Inhibitors of DYRK Kinases
激酶
生物
细胞生物学
作者
Scott Henry Henderson,F.J. Sorrell,James M. Bennett,Oleg Fedorov,Marcus T. Hanley,Paulo H. Godoi,Rafael de Abreu e Souza,Stephen K. Robinson,Iva Navrátilová,J.M. Elkins,Simon E. Ward
标识
DOI:10.2139/ssrn.4689991
摘要
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.