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

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 k inact / K I 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. • The interrogation of GSTO1-1 inhibitor C5-1 as a lead compound was reported. • The X-ray co-crystal structure of C5-1 in complex with GSTO1-1 was solved. • 4 series of C5-1 analogues were synthesized, evaluated biochemically and in cell. • Compounds C5-1 and 10u showed a capacity to attenuate inflammation in mice. • Compounds C5-1 and 10u can significantly enhance the cytotoxicity of cisplatin.