title: 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.
authors.affiliation: 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.|Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
authors.forename: Kavya
authors.initials: K
authors.lastname: Ramkumar
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: Samanta
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
authors.forename: Anahita
authors.initials: A
authors.lastname: Kyani
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
authors.forename: Suhui
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ziemke
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Si
authors.initials: S
authors.lastname: Li
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Krishnapriya
authors.initials: K
authors.lastname: Chinnaswamy
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otake
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prospect, 119991 Moscow, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarovenko
authors.affiliation: Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.|Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Sebolt-Leopold
authors.affiliation: Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.|Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Mats
authors.initials: M
authors.lastname: Ljungman
authors.affiliation: 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.|Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, Michigan 48109, USA.
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D045325:HCT116 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C013874:chloroacetamide; C490476:GSTO1 protein, human; D005982:Glutathione Transferase; D003545:Cysteine