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.
Journal article
Eur J Med Chem
05/04/2024
269
DYRK1A, Imidazo[1,2-b]pyridazines, Selectivity, Humans, Dyrk Kinases, Diabetes Mellitus, Type 2, Protein Kinase Inhibitors, Structure-Activity Relationship, Pyridazines, Iohexol