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

Journal of medicinal chemistry 2021 Jul 08

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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.

Citation

David Lee Walmsley, James B Murray, Pawel Dokurno, Andrew J Massey, Karen Benwell, Andrea Fiumana, Nicolas Foloppe, Stuart Ray, Julia Smith, Allan E Surgenor, Thomas Edmonds, Didier Demarles, Mike Burbridge, Francisco Cruzalegui, Andras Kotschy, Roderick E Hubbard. Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B. Journal of medicinal chemistry. 2021 Jul 08;64(13):8971-8991