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
2024-04-01T00:00:00+00:00
269
Sussex Drug Discovery Centre, University of Sussex, Brighton, BN1 9RH, UK. Electronic address: scott.henderson@benevolent.ai.
Humans, Diabetes Mellitus, Type 2, Iohexol, Pyridazines, Protein Kinase Inhibitors, Structure-Activity Relationship, Dyrk Kinases