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; Simon E Ward

doi:10.1016/j.ejmech.2024.116292

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

Eur J Med Chem. 2024 Apr 5:269:116292. doi: 10.1016/j.ejmech.2024.116292. Epub 2024 Mar 7.

Authors

Affiliations

¹ Sussex Drug Discovery Centre, University of Sussex, Brighton, BN1 9RH, UK. Electronic address: scott.henderson@benevolent.ai.
² Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
³ Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
⁴ Medicines Discovery Institute, Cardiff University, CF10 3AT, UK.
⁵ Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP, 13083-886, Brazil.
⁶ Exscientia, The Schrödinger Building, Oxford Science Park, Oxford, OX4 4GE, UK.
⁷ Exscientia, The Schrödinger Building, Oxford Science Park, Oxford, OX4 4GE, UK; University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
⁸ 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.
⁹ Medicines Discovery Institute, Cardiff University, CF10 3AT, UK. Electronic address: WardS10@cardiff.ac.uk.

PMID: 38479168
DOI: 10.1016/j.ejmech.2024.116292

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.

Keywords: DYRK1A; Imidazo[1,2-b]pyridazines; Selectivity.

MeSH terms

Diabetes Mellitus, Type 2* / drug therapy
Dyrk Kinases
Humans
Iohexol / analogs & derivatives*
Protein Kinase Inhibitors / chemistry
Pyridazines* / chemistry
Structure-Activity Relationship

Substances

Dyrk Kinases
compound 17
Protein Kinase Inhibitors
Pyridazines
Iohexol