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

Eur J Med Chem. 2024 Mar 7;269:116292. doi: 10.1016/j.ejmech.2024.116292. Online ahead of print.ABSTRACTSelective 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.PMID:38479168 | DOI:10.1016/j.ejmech.2024.116292

Source: European Journal of Medicinal Chemistry - March 13, 2024 Category: Chemistry Authors: Scott H Henderson Fiona J Sorrell James M Bennett Oleg Fedorov Marcus T Hanley Paulo H Godoi Roberta Ruela de Sousa Sean Robinson Iva Hopkins Navratilova Jonathan M Elkins Simon E Ward Source Type: research