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

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.
Scott H Henderson 1,  Fiona J Sorrell 2,  James M Bennett 3,  Oleg Fedorov 2,  Marcus T Hanley 4,  Paulo H Godoi 5,  Roberta Ruela de Sousa 5,  Sean Robinson 6,  Iva Hopkins Navratilova 7,  Jonathan M Elkins 8,  Simon E Ward 9
Affiliations

Affiliations

  • 1 Sussex Drug Discovery Centre, University of Sussex, Brighton, BN1 9RH, UK. Electronic address: [email protected].
  • 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: [email protected].
  • 9 Medicines Discovery Institute, Cardiff University, CF10 3AT, UK. Electronic address: [email protected].
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.

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