7EJV

The co-crystal structure of DYRK2 with YK-2-69

Summary for 7EJV

• Entry DOI: 10.2210/pdb7ejv/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 2, [6-[[4-[2-(dimethylamino)-1,3-benzothiazol-6-yl]-5-fluoranyl-pyrimidin-2-yl]amino]pyridin-3-yl]-(4-ethylpiperazin-1-yl)methanone, ... (4 entities in total)
• Functional Keywords: phosphorylase kinase, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 90842.83

Authors

Li, Z.,Xiao, Y.,Yuan, K.,Kuang, W.,Xiuquan, Y.,Yang, P. (deposition date: 2021-04-02, release date: 2022-04-06, Last modification date: 2024-11-13)

Primary citation

Yuan, K.,Li, Z.,Kuang, W.,Wang, X.,Ji, M.,Chen, W.,Ding, J.,Li, J.,Min, W.,Sun, C.,Ye, X.,Lu, M.,Wang, L.,Ge, H.,Jiang, Y.,Hao, H.,Xiao, Y.,Yang, P.
Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer.
Nat Commun, 13:2903-2903, 2022

PubMed 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 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) is 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 discover a highly selective DYRK2 inhibitor YK-2-69, which specifically interacts with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibits more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displays favorable safety properties with a maximal tolerable dose of more than 10,000 mg/kg and pharmacokinetic profiles with 56% bioavailability. In summary, we identify DYRK2 as a potential drug target and verify its critical roles in PCa. Meanwhile, we discover a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.

PubMed: 35614066
DOI: 10.1038/s41467-022-30581-4

Experimental method

X-RAY DIFFRACTION (2.5 Å)