Wenhao Xie,Yuehong Chen,Lulu Jiang,Xinyuan Wu,Zhiyuan Qi,Tianbai Shuai,Mingzhong Yang,Zhiyang Wang,Jinghan Gao,Yingjie Zhu,Xiaojie Lu,Min Huang,Zhibei Qu,Wenfu Tan,Jian Ding,Lu Zhou

Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c02841

Abstract

Gastric cancer is commonly diagnosed at advanced stages and frequently develops multidrug resistance (MDR). Clinical evidence highlights the overexpression of glutathione S-transferase pi 1 (GSTP1) in gastric cancer, which is closely associated with tumor progression and the development of MDR. However, highly potent and selective GSTP1 inhibitors remain scarce. Guided by our previously reported covalent DNA-encoded library (DEL) hit, a series of warhead-removed 1-(azetidin-3-ylmethyl)-1H-benzo[d]imidazole derivatives were obtained as noncovalent GSTP1 inhibitors. The most potent compound, 16n, inhibited GSTP1 enzymatic activity with an IC50 value of 0.79 ± 0.05 μM and demonstrated improved isoform selectivity. In human gastric cancer cells (AGS, HGC27, and NUGC-3), 16n dose-dependently suppressed proliferation and increased intracellular reactive oxygen species levels while decreasing glutathione levels. Importantly, 16n exhibited favorable systemic exposure and achieved 58% tumor growth inhibition with good tolerability in HGC27 xenograft mouse models. Collectively, 16n represents a promising noncovalent GSTP1 inhibitor for the treatment of gastric cancer.