Discovery of Potent, Selective, and Orally Bioavailable DYRK2 Inhibitors for the Treatment of Prostate Cancer

Prostate
cancer (PCa) seriously threatens male health, and targeting
dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2)
has been verified to reduce PCa burden, while the research progress
on the DYRK2 inhibitors was relatively slow. In this work, we discovered
DYRK2 inhibitor 12 (IC50 = 9681 nM) through
virtual screening. Subsequently, we performed systematic structural
optimization to obtain 54 (IC50 = 14 nM).
Compound 54 exhibited high selectivity among 215 kinases
and significantly suppressed the proliferation and metastasis of PCa
cells in vitro. Moreover, compound 54 displayed high safety, favorable bioavailability, and potent tumor
growth inhibitory activity in vivo, which could be
used as a potential candidate in the discovery of novel anti-PCa drugs.