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

Nat Commun. 2022 May 25;13(1):2903. doi: 10.1038/s41467-022-30581-4.

Kai Yuan ^# ¹ ², Zhaoxing Li ^# ¹ ³, Wenbin Kuang ^# ¹ ², Xiao Wang ^# ¹ ², Minghui Ji ¹ ², Weijiao Chen ¹ ², Jiayu Ding ¹ ², Jiaxing Li ¹ ², Wenjian Min ¹ ², Chengliang Sun ¹ ², Xiuquan Ye ¹ ³, Meiling Lu ¹ ⁴, Liping Wang ¹ ², Haixia Ge ⁵, Yuzhang Jiang ⁶, Haiping Hao ⁷ ⁸, Yibei Xiao ⁹ ¹⁰, Peng Yang ¹¹ ¹²

Affiliations

1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 211198, Nanjing, China.
3 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 211198, Nanjing, China.
4 School of Life Science and Technology, China Pharmaceutical University, 211198, Nanjing, China.
5 School of Life Sciences, Huzhou University, 313000, Huzhou, China.
6 Department of Laboratory, Huai'an First People's Hospital, Nanjing Medical University, 223300, Huai'an, Jiangsu, China. jyz8848@163.com.
7 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China. hhp_770505@hotmail.com.
8 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 211198, Nanjing, China. hhp_770505@hotmail.com.
9 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China. yibei.xiao@cpu.edu.cn.
10 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 211198, Nanjing, China. yibei.xiao@cpu.edu.cn.
11 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China. pengyang@cpu.edu.cn.
12 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 211198, Nanjing, China. pengyang@cpu.edu.cn.
# Contributed equally.

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

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-153949

YK-2-69

99.57%, DYRK2 Inhibitor

DYRK

Cancer

Name
Email *

	Sorry, but the email address you supplied was invalid.