Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors

The
kinase DYRK1A is an attractive target for drug discovery programs
due to its implication in multiple diseases. Through a fragment screen,
we identified a simple biaryl compound that is bound to the DYRK1A
ATP site with very high efficiency, although with limited selectivity.
Structure-guided optimization cycles enabled us to convert this fragment
hit into potent and selective DYRK1A inhibitors. Exploiting the structural
differences in DYRK1A and its close homologue DYRK2, we were able
to fine-tune the selectivity of our inhibitors. Our best compounds
potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition
in a model of ovarian carcinoma.