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
  • 1. Australian Translational Medicinal Chemistry Facility, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 2. Australian Translational Medicinal Chemistry Facility, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 3. John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2600, Australia. Electronic address: [email protected].
  • 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: [email protected].
  • 5. Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
  • 6. Institute for Therapeutics Discovery and Development, 717 Delaware Street SE, University of Minnesota, Minneapolis, USA. Electronic address: [email protected].
  • 7. Institute for Therapeutics Discovery and Development, 717 Delaware Street SE, University of Minnesota, Minneapolis, USA. Electronic address: [email protected].
  • 8. Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. Electronic address: [email protected].
  • 9. Institute for Therapeutics Discovery and Development, 717 Delaware Street SE, University of Minnesota, Minneapolis, USA. Electronic address: [email protected].
  • 10. Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia. Electronic address: [email protected].
  • 11. John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2600, Australia. Electronic address: [email protected].
  • 12. Australian Translational Medicinal Chemistry Facility, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
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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