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

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.