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

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 (Lead / Corresponding author), Simon E. Ward (Lead / Corresponding author)

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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.

    Original languageEnglish
    Article number116292
    Number of pages14
    JournalEuropean Journal of Medicinal Chemistry
    Volume269
    Early online date7 Mar 2024
    DOIs
    Publication statusPublished - 5 Apr 2024

    Keywords

    • DYRK1A
    • Imidazo[1,2-b]pyridazines
    • Selectivity

    ASJC Scopus subject areas

    • Pharmacology
    • Drug Discovery
    • Organic Chemistry

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