GSK235 is an orally active and selective allosteric inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1), boasting pIC50 values of 8.45 and 7.59 for human and murine ERAP1, respectively. It demonstrates over 1000-fold selectivity against the highly homologous enzymes ERAP2 and IRAP. GSK235 modulates the immunopeptidome of cancer cells, enhancing their antigenicity, and is applicable in colorectal cancer and arthritis research.

GSK235 (compound 21) at concentrations of 1 μM and 0.61 μM exhibits strong and selective inhibition of ERAP1 and ERAAP enzymes in both human and mouse models over 1 hour and 24 hours. In the HeLa antigen presentation assay, GSK235 shows a pIC50 value of 7.25. When administered at 1 µM for 30 days, GSK235 influences the production of various immunopeptides in CT26 tumor cells, notably increasing peptide chain lengths such as 10-mers and 11-mers while reducing 9-mers and 8-mers. GSK235 shows no activity on the hERG channel.

GSK235 (compound 21) administered orally at doses of 30, 90, and 270 mg/kg twice daily for 17 days demonstrates a dose-dependent reduction in tumor growth and modulation of the immunopeptidome in the CT26 syngeneic mouse model. Additionally, GSK235 at the same dosages, given from day 18 to day 36, reduces arthritis scores and immune activation in a dose-dependent manner in the collagen-induced arthritis (CIA) mouse model, without evidence of exacerbated autoimmunity.