Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

• DOI: 10.1016/j.ejmech.2024.116292
• Publication Date: 2024-03-07T08:25:39Z
• Authors: Scott H. Henderson; Fiona J. Sorrell; James M. Bennett; Oleg Fedorov; Marcus T. Hanley; Paulo H. Godoi; Roberta Ruela de ...; Sean Robinson; Iva Hopkins Navra...; Jonathan M. Elkins; Simon E. Ward
• Keywords: /dk/atira/pure/subjectarea/asjc/1600/1605; name=Organic Chemistry; /dk/atira/pure/subjectarea/asjc/3000/3004; Selectivity; DYRK1A; /dk/atira/pure/subjectarea/asjc/3000/3002; name=Drug Discovery; name=Pharmacology; 540; Imidazo[1,2-b]pyridazines

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.