Mining Public Domain Data to Develop Selective DYRK1A Inhibitors

  • ACS Med Chem Lett. 2020 Jun 30;11(8):1620-1626. doi: 10.1021/acsmedchemlett.0c00279.
Scott H Henderson  1 ,  Fiona Sorrell  2 ,  James Bennett  3 ,  Marcus T Hanley  4 ,  Sean Robinson  5 ,  Iva Hopkins Navratilova  5  6 ,  Jonathan M Elkins  2  7 ,  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. Exscientia, The Schrödinger Building, Oxford Science Park, Oxford OX4 4GE, U.K.
  • 6. University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • 7. Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP 13083-886, Brazil.
PMID: 32832032 DOI: 10.1021/acsmedchemlett.0c00279
Abstract

Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor.

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