6-(4-methoxyphenyl)pyrimidine-2-4-diamine and Ovarian-Neoplasms

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

Topics: Adenosine Triphosphate; Animals; Binding Sites; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase 9; Drug Design; Drug Evaluation, Preclinical; Dyrk Kinases; Female; Humans; Mice; Mice, Nude; Molecular Docking Simulation; Ovarian Neoplasms; Phosphorylation; Protein Isoforms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyrimidines; Structure-Activity Relationship