The serine/threonine kinase DYRK1A has been implicated in the 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, an elevated level of 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.

A collaboration between Vernalis Research and Servier used a ligand-observed NMR screen to identify fragments that bound competitively at the ATP site of DYRK1A which led to two series of optimised, potent inhibitors of DYRK1A.  These are described in two publications:

Walmsley, D.L. et al., J. Med. Chem. 2021, 64, 8971

Weber, C. et al., J. Med. Chem. 2021, 64, 6745

One example compound is the highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor 34 which showed in vivo activity in a tumor model. These inhibitors provide useful tool compounds for further exploration of the effect of DYRK1A inhibition in models of disease.

Structure of 34 (PDB code: 7A5N) bound to Dyrk1A