喹唑啉衍生物kzl052通过靶向WRN解旋酶稳定DNA复制叉来抑制前列腺癌。

Quinazoline Derivative kzl052 Suppresses Prostate Cancer by Targeting WRN Helicase to Stabilize DNA Replication Forks.

作者信息

Yu Jia, Yu Gang, Cheng Sha, Hu Liangliang, Zan Ningning, Xu Bixue, Cao Ying, Luo Heng

机构信息

Medical College, Guizhou University, Guiyang 550025, China.

State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 550014, China.

出版信息

Int J Mol Sci. 2025 Jun 25;26(13):6093. doi: 10.3390/ijms26136093.

DOI:10.3390/ijms26136093

PMID:40649870

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12249509/

Abstract

WRN helicases play a key role in DNA replication, repair, and other processes in a variety of tumors. It has become one of the hot targets of genotoxic drugs, but the effect and mechanism of targeting WRN against prostate cancer is still unclear. In our previous study, we found a quinazoline compound kzl052, which has a WRN-dependent inhibitory effect on prostate cancer cells, but its molecular mechanism needs to be further explored. In this study, kzl052 significantly inhibited the growth of PC3 (IC = 0.39 ± 0.01 μM) and LNCaP (IC = 0.11 ± 0.01 μM) cells in vitro and showed a good inhibition effect on PCa in vivo. It inhibits PC3 cell growth by binding to WRN proteins and affecting its non-enzymatic function. Then the mechanism of kzl052 against prostate cancer progression was revealed to be by regulating the stability of DNA replication forks and the RB pathway. This study will provide a theoretical basis and treatment strategy for targeting WRN helicase in the treatment of prostate cancer.

摘要

WRN解旋酶在多种肿瘤的DNA复制、修复及其他过程中发挥关键作用。它已成为基因毒性药物的热门靶点之一，但靶向WRN治疗前列腺癌的效果和机制仍不清楚。在我们之前的研究中，我们发现了一种喹唑啉化合物kzl052，其对前列腺癌细胞具有WRN依赖性抑制作用，但其分子机制有待进一步探索。在本研究中，kzl052在体外显著抑制PC3（IC = 0.39 ± 0.01 μM）和LNCaP（IC = 0.11 ± 0.01 μM）细胞的生长，并且在体内对前列腺癌显示出良好的抑制效果。它通过与WRN蛋白结合并影响其非酶功能来抑制PC3细胞生长。随后揭示了kzl052对抗前列腺癌进展的机制是通过调节DNA复制叉的稳定性和RB通路。本研究将为靶向WRN解旋酶治疗前列腺癌提供理论依据和治疗策略。