2. Academic Validation
  3. Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

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

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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