2. Academic Validation
  3. Quinazoline derivatives inhibit cell growth of prostate cancer as a WRN helicase dependent manner by regulating DNA damage repair and microsatellite instability

Quinazoline derivatives inhibit cell growth of prostate cancer as a WRN helicase dependent manner by regulating DNA damage repair and microsatellite instability

  • Bioorg Chem. 2024 Dec:153:107963. doi: 10.1016/j.bioorg.2024.107963.
Jia Yu 1,  Yunyun Zhou 2,  Guangyan Liang 1,  Sha Cheng 1,  Jiaomei Wei 3,  Huimin Li 2,  Xinyu Liu 2,  Chang You 3,  Mengsha Mao 2,  Mashaal Ahmad 4,  Gang Yu 5,  Bixue Xu 6,  Heng Luo 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China; School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China.
  • 3 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China; College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China. Electronic address: 820485158@qq.com.
  • 6 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China. Electronic address: bixue_xu@126.com.
  • 7 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China. Electronic address: luo_heng@gmc.edu.cn.
PMID: 39571305 DOI: 10.1016/j.bioorg.2024.107963
Abstract

WRN helicase is a crucial target of synthetic death in Cancer and has a unique advantage in the treatment of microsatellite unstable cancers. Our previous studies have found that quinazoline derivatives showed the WRN-dependent antiproliferative activity. In this study, a series of new quinazoline derivatives were designed and synthesized by optimizing the structure, and evaluating the targeting and sensitivity to WRN helicase. Cell growth inhibition experiments on WRN overexpressing PC3 cells (PC3-WRN) showed that the antiproliferative activity of some compounds was significantly dependent on WRN helicase. Moreover, the antitumor activity of 9in vivo was significantly decreased in the nude mouse model constructed with WRN knockdown PC3 cells (PC3-shWRN) compare (P < 0.01) to the control group. The molecular docking and CETSA results showed that 9 directly binds to WRN protein. Mechanism studies have confirmed that 9 targeted WRN, and may affect the binding between WRN and Other key regulators, to destroy the repair function and regulate genomic stability. In addition, 9 also has suitable pharmacokinetic parameters and low toxicity in vivo. This result indicates that the quinazoline derivative 9 could be a novel WRN function inhibitor for the treatment of prostate Cancer.

Keywords

DNA damage repair; Microsatellite instability; Prostate cancer; Quinzoline derivatives; WRN Helicase.

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