Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor

Abstract

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.

Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties

“…By contrast, the compounds possessing a chloroacetamide group, RA371 and Structure-function analyses of candidate RPN13 inhibitors RA375 (compounds 36 and 42 in S1 Table), were the most potent in the series. Although chloroacetamide is the active component of several candidate GSTO1 inhibitors [28,29], in a competition assay using KT59 as a click chemistry probe [28], there was no evidence of RA375 competing its binding to GSTO1 (S1A Fig).…”

“…Because of the potential for competition with, or inactivation by, cellular glutathione, we also tested incorporation of an additional warhead, including chloroacetamide, intended to lower cellular glutathione levels [28,29], thereby limiting inactivation of our chalcone-based RPN13 inhibitors and increasing oxidative stress and their antitumor potency.…”

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

“…Microsomal GST consists of three isoforms encoded by a single gene located on chromosome 12 that are involved in the endogenous metabolism of leukotrienes and prostaglandins . Cytosolic GST represents a genetic polymorphism and is classified into seven classes – alpha, mu, omega, pi, sigma, theta and zeta . In humans, cytosolic GSTs are encoded by seven different chromosomes but share ~ 30% sequence identity .…”

“…Cytosolic GST represents a genetic polymorphism and is classified into seven classes – alpha, mu, omega, pi, sigma, theta and zeta . In humans, cytosolic GSTs are encoded by seven different chromosomes but share ~ 30% sequence identity . There are signs of both structural and functional redundancies between isozyme family members .…”

Upregulated glutathione transferase omega-1 correlates with progression of urinary bladder carcinoma

“…Despite the difficulties in this field related to the complexity of biochemical pathways, an understanding of the relationship between redox homeostasis and TCC progression could lead to the development of drugs able to interact with such molecular processes, thereby expanding the therapeutic strategy against TCC. Ramkumar et al [25] have reported on the development of series of chloroacetamide-containing GSTO1 inhibitors that suppress cancer cell growth, increase the cytotoxic effects of cisplatin, and inhibit tumor growth in colon cancer models as single agent, supporting the notion of GSTO1 as a potential new target in oncology.…”