论文｜Lei, H.; Jiang, Y.; Liu, J.; Zhang, W.; Meng, F.; Mou, J.; Liu, W.; Lei, P.; Xiong, R.; Xu, Z.; Zhang, H.; Wang, Y.; Li, G.-B.; Yang, L.; Wang, H.-L: Structure-activity relationship studies of 3,4-disubstitued indole-2-ketone derivatives identify a potent glutaminyl cyclase inhibitor with antitumor activity against breast cancer

本文（Structure-activity relationship studies of 3,4-disubstitued indole-2-ketone derivatives identify a potent glutaminyl cyclase inhibitor with antitumor activity against breast cancer）原载Chinese Chemical Letters，由四川大学李国菠教授等科研人员创作，系四川智慧社会智能治理重点实验室智慧法治研究所的系列学术成果。本网站后续将持续分享实验室的系列学术成果，欢迎大家阅读。

Abstract: Glutaminyl cyclase (QC), a key enzyme catalyzing the pyroglutamate modification of bioactive peptides, has emerged as a promising pharmacological target in cancer and other human diseases. Inhibition of QC activity represents a potential therapeutic strategy for diseases associated with QC dysregulation, suggesting that QC inhibitors might be as promising therapeutic approach for these diseases. Building upon our previous lead compound 1 (half maximal inhibitory concentration (IC50): Golgi resident QC (gQC), 3.22 µmol/L; secretory QC (sQC), 4.04 µmol/L), we performed systematic structural optimization to develop novel 3,4-disubstituted indole-2-ketone derivatives. Structure-activity relationship (SAR) studies identified highly active gQC and sQC inhibitors (compounds 24, 28, and 29) with significantly enhanced QC inhibitory activity. Among them, 28 exhibited superior inhibitory activity against gQC (IC50 = 0.095 µmol/L) compared to sQC (IC50 = 1.33 µmol/L), and could most significantly improve the thermal stability of gQC protein. Using compound 17 with similar structure but 130 times lower gQC inhibitory activity than 28 as a negative control, the in vitro anti-tumor activity study found that 28 can bind to gQC in MDA-MB-231 breast cancer cells and significantly inhibit the growth and migration, by affecting cell proliferation and inducing G0/G1 phase cell cycle arrest. In nude mice bearing MDA-MB-231 cell xenograft, intratumor injection of 28 (25 mg/kg) produced 40.6 % inhibition rates. This work not only provides structural basis and new leads for drug discovery targeting QC, but also presents compelling evidence supporting QC, especially gQC as a potential target for breast cancer therapy.

Lei, H.; Jiang, Y.; Liu, J.; Zhang, W.; Meng, F.; Mou, J.; Liu, W.; Lei, P.; Xiong, R.; Xu, Z.; Zhang, H.; Wang, Y.; Li, G.-B.; Yang, L.; Wang, H.-L. Structure-activity relationship studies of 3,4-disubstitued indole-2-ketone derivatives identify a potent glutaminyl cyclase inhibitor with antitumor activity against breast cancer. Chinese Chemical Letters 2025, 111511. （论文下载）