MIPS research summary: Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors

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Glutathione transferase omega-1 (GSTO1-1) is a member of the omega class glutathione transferase, having a cysteine active site which is exclusive to this class of enzymes. Besides displaying several atypical activities including S-(phenacyl) glutathione reductase and deglutathionylase activities, GSTO1-1 was recently found to play a key role in the Toll-like Receptor 4-mediated pro-inflammatory pathway, as well as to regulate NLRP3 inflammasome by deglutathionylating NEK7. By inhibiting GSTO1-1, broad inflammatory conditions such as sepsis could potentially be targeted. GSTO1-1 was also reported to be a potential drug target for age-related macular degeneration and diverse human cancers. By far, several small molecules have been reported as GSTO1-1 inhibitors, but none of them have progressed through preclinical development.

In this work, MIPS researchers Cathy Xie, Girdhar Deora and Jonathan Baell selected a reported GSTO1-1 inhibitor C1-27 as the lead compound, and conducted a comprehensive SAR investigation on it to identify highly potent novel GSTO1-1 inhibitors, both in vitro and in cell. Throughout the SAR investigation, 32 analogues were synthesized via different chemical modifications on the scaffold, which led to the identification of both favourable and unfavourable substitutions at 3 distinct regions of the molecule after the test of their IC50 values in the 4-NPG assay. As covalent inhibitors, the kinact/KI values of selected compounds were also tested with an adapted 4-NPG assay, which is the first time for this index to be determined for GSTO1-1 inhibitors. Cellular analysis, pharmacokinetics analysis and crystallographic analysis on key compounds were also performed.

As a result, compound 25 in this series was identified as a better GSTO1-1 inhibitor than C1-27, being significantly more active than C1-27 in cell and displaying a much slower elimination than C1-27 while maintaining a similarly fast absorption and high exposure in mice.

Article: Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors

MIPS Authors: Cathy Xie, Girdhar Deora & Jonathan Baell

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