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

Henderson, Scott, Sorrell, Fiona, Bennett, James, Fedorov, Oleg, Hanley, Marcus, Godoi, Paulo, de Sousa, Roberta Ruela, Robinson, Sean, Hopkins Navratilova, Iva, Elkins, Jonathan and Ward, Simon ORCID: https://orcid.org/0000-0002-8745-8377 2024. Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases. European Journal of Medicinal Chemistry 269 , 16292. 10.1016/j.ejmech.2024.116292

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
Publisher:	Elsevier
ISSN:	0223-5234
Date of First Compliant Deposit:	23 May 2024
Date of Acceptance:	27 February 2024
Last Modified:	23 May 2024 14:00
URI:	https://orca.cardiff.ac.uk/id/eprint/167926

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