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

Autor: Henderson SH; Sussex Drug Discovery Centre, University of Sussex, Brighton, BN1 9RH, UK. Electronic address: scott.henderson@benevolent.ai., Sorrell FJ; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK., Bennett JM; Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK., Fedorov O; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK., Hanley MT; Medicines Discovery Institute, Cardiff University, CF10 3AT, UK., Godoi PH; Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP, 13083-886, Brazil., Ruela de Sousa R; Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP, 13083-886, Brazil., Robinson S; Exscientia, The Schrödinger Building, Oxford Science Park, Oxford, OX4 4GE, UK., Navratilova IH; Exscientia, The Schrödinger Building, Oxford Science Park, Oxford, OX4 4GE, UK; University of Dundee, Dow Street, Dundee, DD1 5EH, UK., Elkins JM; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK; Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP, 13083-886, Brazil. Electronic address: jon.elkins@cmd.ox.ac.uk., Ward SE; Medicines Discovery Institute, Cardiff University, CF10 3AT, UK. Electronic address: WardS10@cardiff.ac.uk.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Apr 05; Vol. 269, pp. 116292. Date of Electronic Publication: 2024 Mar 07.
DOI: 10.1016/j.ejmech.2024.116292
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare no financial competing interests.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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