Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

  • J Med Chem. 2021 Aug 12;64(15):11709-11728. doi: 10.1021/acs.jmedchem.1c01115.
Scott H Henderson  1 ,  Fiona Sorrell  2 ,  James Bennett  3 ,  Oleg Fedorov  3 ,  Marcus T Hanley  4 ,  Paulo H Godoi  5 ,  Roberta Ruela de Sousa  5 ,  Sean Robinson  6 ,  Alexander Ashall-Kelly  4 ,  Iva Hopkins Navratilova  6  7 ,  Daryl S Walter  8 ,  Jonathan M Elkins  2  5 ,  Simon E Ward  4
Affiliations
  • 1. Sussex Drug Discovery Centre, University of Sussex, Brighton BN1 9RH, U.K.
  • 2. Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
  • 3. Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.
  • 4. Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, U.K.
  • 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, U.K.
  • 7. University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • 8. Evotec (UK) Ltd., 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
PMID: 34342227 DOI: 10.1021/acs.jmedchem.1c01115
Abstract

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

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