2. Academic Validation
  3. Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor

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

  • Nat Commun. 2016 Oct 5;7:13084. doi: 10.1038/ncomms13084.
Kavya Ramkumar 1 2 3,  Soma Samanta 2 3,  Anahita Kyani 2 3,  Suhui Yang 2 3,  Shuzo Tamura 2 3,  Elizabeth Ziemke 3 4,  Jeanne A Stuckey 5,  Si Li 1,  Krishnapriya Chinnaswamy 5,  Hiroyuki Otake 1,  Bikash Debnath 2 3,  Vladimir Yarovenko 6,  Judith S Sebolt-Leopold 3 4 7,  Mats Ljungman 3 8,  Nouri Neamati 1 2 3
Affiliations

Affiliations

  • 1 Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90033, USA.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
  • 3 Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
  • 4 Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
  • 5 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • 6 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prospect, 119991 Moscow, Russia.
  • 7 Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
  • 8 Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
PMID: 27703239 DOI: 10.1038/ncomms13084
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.

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