Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B

  • J Med Chem. 2021 Jul 8;64(13):8971-8991. doi: 10.1021/acs.jmedchem.1c00024.
David Lee Walmsley  1 ,  James B Murray  1 ,  Pawel Dokurno  1 ,  Andrew J Massey  1 ,  Karen Benwell  1 ,  Andrea Fiumana  1 ,  Nicolas Foloppe  1 ,  Stuart Ray  1 ,  Julia Smith  1 ,  Allan E Surgenor  1 ,  Thomas Edmonds  2 ,  Didier Demarles  3 ,  Mike Burbridge  2 ,  Francisco Cruzalegui  2 ,  Andras Kotschy  4 ,  Roderick E Hubbard  1
Affiliations
  • 1. Vernalis (R&D) Ltd., Granta Park, Cambridge CB21 6GB, U.K.
  • 2. Institut de Recherches Servier, 125 Chemin de Ronde, Croissy-sur-Seine 78290, France.
  • 3. Technologie Servier, 27 Rue Eugène Vignat, Orleans 45000, France.
  • 4. Servier Research Institute of Medicinal Chemistry, Záhony u. 7., Budapest H-1031, Hungary.
PMID: 34143631 DOI: 10.1021/acs.jmedchem.1c00024
Abstract

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with Cancer progression, including cell cycle control, DNA damage repair, protection from Apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

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