2. Academic Validation
  3. Hit to lead optimization of the 4-trifluoromethylquinoline derivatives as novel SGK1 inhibitors with potent anti-prostate cancer activity

Hit to lead optimization of the 4-trifluoromethylquinoline derivatives as novel SGK1 inhibitors with potent anti-prostate cancer activity

  • Eur J Med Chem. 2025 Apr 5:287:117336. doi: 10.1016/j.ejmech.2025.117336.
Cheng Li 1,  Sha Cheng 2,  Jia Yu 2,  Qian Zheng 3,  Gang Yu 2,  Mei Xu 2,  Xueling Meng 2,  Xiaoping Zeng 2,  Kun Liu 2,  Bixue Xu 4,  Heng Luo 5,  Guangcan Xu 6
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; Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, 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.
  • 3 Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
  • 4 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.
  • 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: luo_heng@gmc.edu.cn.
  • 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: xgc0707@163.com.
PMID: 39908792 DOI: 10.1016/j.ejmech.2025.117336
Abstract

Prostate Cancer (PCa) remains a significant health concern for males, and serum/glucocorticoid-regulated kinase-1 (SGK1) plays a crucial role in its pathogenesis. This provides a promising target for the development of novel therapies against PCa. Herein, we reported the structural optimization of the hit compound H1, which was discovered in our previous work as an SGK1 Inhibitor. Based on docking research for the active binding conformation of compound H1, a series of novel 4-trifluoromethyl quinoline derivatives were developed by replacing the 6-methoxy group in the quinoline skeleton of compound H1 with a larger aryl ring to occupy the hinge region of SGK1. Among them, compound 12f showed the strongest SGK1 inhibitory potency, with an IC50 value of 0.39 μM, representing a 7.8-fold improvement over compound H1. Molecular docking studies revealed that the 6-methoxyphenylamine moiety of compound 12f effectively extends into the hinge region of SGK1, establishing a crucial hydrogen bonding interaction with Glu183 that enhances its biological potency. In vivo, compound 12f effectively suppressed tumor growth in the PC3 xenograft model in BALB/c nude mice without inducing any observable toxicity. Moreover, mechanistic studies showed that compound 12f hindered PC3 cell migration and invasion, improved the thermal stability of SGK1 protein in PC3 cells, decreased SGK1 protein levels in tumor tissues, and effectively inhibited the phosphorylation of SGK1 and its substrates in PC3 cells in a dose- and time-dependent manner. In summary, the results of this study highlight the potential of 12f as a lead compound for further optimization in the development of new therapies against PCa targeting SGK1.

Keywords

4-Trifluoromethylquinoline; Anti-prostate cancer; Hinge region; Molecular docking; SGK1 inhibitors; Structural optimization.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170933
    SGK1 Inhibitor
    SGK