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

Kavya Ramkumar, Soma Samanta, Anahita Kyani, Suhui Yang, Shuzo Tamura, Elizabeth Ziemke, Jeanne A. Stuckey, Si Li, Krishnapriya Chinnaswamy, Hiroyuki Otake, Bikash Debnath, Vladimir Yarovenko, Judith S. Sebolt-Leopold, Mats Ljungman and Nouri Neamati ()
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Kavya Ramkumar: School of Pharmacy, University of Southern California
Soma Samanta: College of Pharmacy, University of Michigan
Anahita Kyani: College of Pharmacy, University of Michigan
Suhui Yang: College of Pharmacy, University of Michigan
Shuzo Tamura: College of Pharmacy, University of Michigan
Elizabeth Ziemke: Translational Oncology Program, University of Michigan
Jeanne A. Stuckey: Life Sciences Institute, University of Michigan
Si Li: School of Pharmacy, University of Southern California
Krishnapriya Chinnaswamy: Life Sciences Institute, University of Michigan
Hiroyuki Otake: School of Pharmacy, University of Southern California
Bikash Debnath: College of Pharmacy, University of Michigan
Vladimir Yarovenko: N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
Judith S. Sebolt-Leopold: Translational Oncology Program, University of Michigan
Mats Ljungman: Translational Oncology Program, University of Michigan
Nouri Neamati: School of Pharmacy, University of Southern California

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13084

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