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

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.