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  3. Development of potent glutathione transferase Omega-1 inhibitors with applications in inflammation and cancer therapy

Development of potent glutathione transferase Omega-1 inhibitors with applications in inflammation and cancer therapy

  • Eur J Med Chem. 2025 Dec 5:299:118072. doi: 10.1016/j.ejmech.2025.118072.
Yiyue Xie 1,  Yuji Nakano 2,  Padmaja Tummala 3,  Aaron J Oakley 4,  Adi Suwandi 5,  Matthew E Cuellar 6,  Jessica M Strasser 7,  Jayme L Dahlin 8,  Michael A Walters 9,  Marco G Casarotto 10,  Philip G Board 11,  Jonathan B Baell 12
Affiliations

Affiliations

  • 1 Australian Translational Medicinal Chemistry Facility, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: cathy.xie@monash.edu.
  • 2 Australian Translational Medicinal Chemistry Facility, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: yujinakano1991@gmail.com.
  • 3 John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2600, Australia. Electronic address: padmaja.tummala@anu.edu.au.
  • 4 Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, and Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia. Electronic address: aarono@uow.edu.au.
  • 5 Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: adi.suwandi@monash.edu.
  • 6 Institute for Therapeutics Discovery and Development, 717 Delaware Street SE, University of Minnesota, Minneapolis, USA. Electronic address: cuellarmitunc@gmail.com.
  • 7 Institute for Therapeutics Discovery and Development, 717 Delaware Street SE, University of Minnesota, Minneapolis, USA. Electronic address: strasser.jessica@gmail.com.
  • 8 Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. Electronic address: jaymedahlin.sci@gmail.com.
  • 9 Institute for Therapeutics Discovery and Development, 717 Delaware Street SE, University of Minnesota, Minneapolis, USA. Electronic address: mwalters@umn.edu.
  • 10 Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia. Electronic address: marco.casarotto@anu.edu.au.
  • 11 John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2600, Australia. Electronic address: philip.board@anu.edu.au.
  • 12 Australian Translational Medicinal Chemistry Facility, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: jbaell29@gmail.com.
PMID: 40886681 DOI: 10.1016/j.ejmech.2025.118072
Abstract

Glutathione transferase Omega-1 (GSTO1-1) plays a key role in the activation of the NLRP3 inflammasome. Consequently, it is involved in the pathology of multiple inflammatory conditions as well as Cancer. Small-molecule inhibitors that bind covalently to its active-site cysteine have been developed as potential therapeutics. In this study, the X-ray co-crystal structure of the reported GSTO1-1 inhibitor C5-1 in complex with GSTO1-1 was solved, and used to elaborate a comprehensive SAR analysis of C5-1. The inhibitory profile of compounds was evaluated in a spectrophotometric assay with purified recombinant GSTO1-1 and in a cell-based assay measuring IL-1β release. The kinact/KI values of selected covalent inhibitors were determined as well as the biochemical selectivity of these compounds for GSTO1-1 over GSTO2-2, GSTA1-1 and GSTP1-1. The C5-1 chemotype was assessed to be a useful biochemical tool for GSTO1-1 inhibitor development with our analysis revealing that compound 10u to be the most potent GSTO1-1 inhibitor identified in this study. Both C5-1 and 10u showed a capacity to attenuate inflammation in mice and to significantly enhance the cytotoxicity of cisplatin, suggesting their future potential application in the treatment of inflammation and Cancer.

Keywords

Anti-Cancer; Anti-inflammation; Covalent inhibitor; GSTO1-1 inhibitor; Glutathione transferase Omega-1; NLRP3 inflammasome; SAR.

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