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
  • 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.