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.

Automated summary

The kinase DYRK1A has been identified as a promising target for drug discovery, and a biaryl compound was developed through fragment screening to efficiently bind to its ATP site. Structural optimization cycles resulted in the transformation of this compound into potent and selective DYRK1A inhibitors, with a focus on fine-tuning selectivity by exploiting structural differences with DYRK2. These inhibitors demonstrated potent inhibition of DYRK1A in cell culture and in vivo, with drug-like properties and dose-dependent tumor growth inhibition in an ovarian carcinoma model.