Structure-optimized 4-trifluoromethylquinoline derivatives: Dual enhancement of SGK1 inhibition and anti-prostate cancer efficacy

  • Bioorg Chem. 2026 May 28:180:110032. doi: 10.1016/j.bioorg.2026.110032.
Yafang Zhou  1 ,  Sha Cheng  2 ,  Cheng Li  1 ,  Xinyu Liu  2 ,  Jia Yu  2 ,  Gang Yu  2 ,  Ping Yi  2 ,  Xiaoping Zeng  2 ,  Wei Tu  2 ,  Xueling Meng  2 ,  Kun Liu  2 ,  Xiaolin Peng  2 ,  Ningning Zan  2 ,  Heng Luo  3 ,  Bixue Xu  4 ,  Guangcan Xu  5
Affiliations
  • 1. School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Natural Products Research Center of Guizhou Province, Guizhou Medical University, Guiyang 550014, China.
  • 2. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Natural Products Research Center of Guizhou Province, Guizhou Medical University, Guiyang 550014, China.
  • 3. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Natural Products Research Center of Guizhou Province, Guizhou Medical University, Guiyang 550014, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Natural Products Research Center of Guizhou Province, Guizhou Medical University, Guiyang 550014, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Natural Products Research Center of Guizhou Province, Guizhou Medical University, Guiyang 550014, China. Electronic address: [email protected].
PMID: 42242016 DOI: 10.1016/j.bioorg.2026.110032
Abstract

Based on the previously identified lead compound H1, a 4-trifluoromethyl-2-arylaminoquinoline derivative, this study designed and synthesized 13 novel derivatives to enrich structural diversity and optimize bioactivity, and further evaluated their SGK1 inhibitory activity and anti-prostate Cancer effects. The results revealed that compound 7h exhibited stronger SGK1 inhibitory ability and superior in vitro antitumor activity, as well as better SGK family selectivity than H1. Mechanistic experiments verified that 7h induced cell Apoptosis, caused S-phase cell cycle arrest and inhibited cell migration in a concentration or time-dependent manner. It directly bound to and stabilized SGK1, and effectively downregulated the phosphorylation of downstream MDM2 and GSK-3β. Molecular docking indicated that 7h functioned as an ATP-competitive inhibitor by targeting the ATP-binding pocket of SGK1. The methylene modification of 7h strengthened its binding interaction with SGK1, which accounted for its enhanced bioactivity. Moreover, 7h possessed favorable ADME properties with high oral absorption, qualified blood-brain barrier penetration and no CYP inhibition risk. Collectively, the structurally optimized compound 7h serves as a high-efficiency and druggable lead candidate, providing a reliable foundation for the further development of novel anti-prostate Cancer drugs.

Keywords
4-Trifluoromethylquinoline derivatives; ADME prediction; Anti-prostate cancer; SGK1 inhibitors; Structural optimization.
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