Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) with a highly selective inhibitor for the treatment of prostate cancer

Abstract

Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide, and hormonal therapy plays a key role in the treatment of PCa. However, the inevitable drug resistance of hormonal therapy makes it urgent and necessary to identify novel targets for PCa treatment. Herein, dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found and confirmed to be highly expressed in the PCa tissues and cells, and knock-down of DYRK2 remarkably reduces PCa burden in vitro and in vivo. On the base of DYRK2 acting as a promising target, we further discovered a highly selective DYRK2 inhibitor YK-2-69 and solved its co-crystal structure. Especially, YK-2-69 displayed great selectivity over 370 kinases and exhibited more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displayed excellent safety properties with maximal tolerable dose of more than 10,000 mg/kg and great pharmacokinetic profiles with 55.78% bioavailability. In summary, we identified DYRK2 as a novel drug target and verified its critical roles in PCa. Meanwhile, we discovered a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.