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

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. Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Citation

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. Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases. European journal of medicinal chemistry. 2024 Apr 05;269:116292

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PMID: 38479168

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