Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90033, USA.
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
Nat Commun. 2016 Oct 5;7:13084. doi: 10.1038/ncomms13084.
Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology. We report on the development and characterization of a series of chloroacetamide-containing potent GSTO1 inhibitors. Co-crystal structures of GSTO1 with our inhibitors demonstrate covalent binding to the active site cysteine. These potent GSTO1 inhibitors suppress cancer cell growth, enhance the cytotoxic effects of cisplatin and inhibit tumour growth in colon cancer models as single agent. Bru-seq-based transcription profiling unravelled novel roles for GSTO1 in cholesterol metabolism, oxidative and endoplasmic stress responses, cytoskeleton and cell migration. Our findings demonstrate the therapeutic utility of GSTO1 inhibitors as anticancer agents and identify the novel cellular pathways under GSTO1 regulation in colorectal cancer.
谷胱甘肽 S-转移酶 ω1（GSTO1）是一种非典型的 GST 同工酶，在多种癌症中过度表达，并与耐药性有关。目前，没有针对 GSTO1 的小分子药物处于临床开发阶段。在这里，我们通过 siRNA 沉默 GSTO1 显著损害癌细胞活力，验证 GSTO1 是肿瘤学中的一个潜在新靶点。我们报告了一系列含氯乙酰胺的有效 GSTO1 抑制剂的开发和表征。GSTO1 与我们抑制剂的共晶结构证明了与活性位点半胱氨酸的共价结合。这些有效的 GSTO1 抑制剂抑制癌细胞生长，增强顺铂的细胞毒性作用，并作为单一药物抑制结肠癌模型中的肿瘤生长。基于 Bru-seq 的转录谱揭示了 GSTO1 在胆固醇代谢、氧化和内质网应激反应、细胞骨架和细胞迁移中的新作用。我们的研究结果表明 GSTO1 抑制剂作为抗癌药物的治疗效用，并确定了 GSTO1 在结直肠癌中调节的新的细胞通路。
