Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer

Prostate cancer (PCa) is a common male cancer with high
incidence
and mortality, and hormonal therapy as the major treatment for PCa
patients is troubled by the inevitable resistance that makes us identify
novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated
kinase 2 (DYRK2) was found to be an effective target for the treatment
of PCa, but the research on its inhibitors is rather little. In this
work, a potent DYRK2 inhibitor 43 (IC50 =
0.6 nM) was acquired through virtual screening and structural optimization,
which displayed high selectivity among 205 kinases; meanwhile, detailed
interactions of 43 with DYRK2 were illustrated by the
cocrystal. Furthermore, 43 possessed great water solubility
(29.5 mg/mL), favorable safety properties (LD50 > 10,000
mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further
preclinical studies.