| 描述信息 |
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 reduced 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, which specifically interacted with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibited more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displayed excellent safety properties with a maximal tolerable dose of more than 10,000 mg/kg and great pharmacokinetic profiles with 56% 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. |
