Li Cheng, Cheng Sha, Yu Jia, Zheng Qian, Yu Gang, Xu Mei, Meng Xueling, Zeng Xiaoping, Liu Kun, Xu Bixue, Luo Heng, Xu Guangcan
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.
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.
Eur J Med Chem. 2025 Apr 5;287:117336. doi: 10.1016/j.ejmech.2025.117336. Epub 2025 Jan 31.
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 IC 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.
前列腺癌（PCa）仍然是男性健康的重大问题，血清/糖皮质激素调节激酶-1（SGK1）在其发病机制中起着关键作用。这为开发针对PCa的新型疗法提供了一个有前景的靶点。在此，我们报道了命中化合物H1的结构优化，该化合物在我们之前的工作中被发现是一种SGK1抑制剂。基于对化合物H1活性结合构象的对接研究，通过用更大的芳环取代化合物H1喹啉骨架中的6-甲氧基，开发了一系列新型4-三氟甲基喹啉衍生物，以占据SGK1的铰链区。其中，化合物12f表现出最强的SGK1抑制效力，IC值为0.39 μM，比化合物H1提高了7.8倍。分子对接研究表明，化合物12f的6-甲氧基苯胺部分有效地延伸到SGK1的铰链区，与Glu183建立了关键的氢键相互作用，从而增强了其生物活性。在体内，化合物12f有效地抑制了BALB/c裸鼠PC3异种移植模型中的肿瘤生长，且未诱导任何可观察到的毒性。此外，机制研究表明，化合物12f阻碍了PC3细胞的迁移和侵袭，提高了PC3细胞中SGK1蛋白的热稳定性，降低了肿瘤组织中SGK1蛋白的水平，并以剂量和时间依赖性方式有效抑制了PC3细胞中SGK1及其底物的磷酸化。总之，本研究结果突出了12f作为一种先导化合物在开发针对SGK1的PCa新疗法中进一步优化的潜力。
