A Glutathione S-Transferase Pi Molecular Glue Tethers Splicing Factors and Remodels Cell Metabolism

Here, we discovered a tyrosine-reactive GSTP1 inhibitor can function as a molecular glue via a ligand induced protein tethering (LIPT) mechanism. Electrophilic modification of GSTP1 results in disulfide tethering of protein complexes in live cells, and these protein-protein interactions (PPIs) can be reversed using reducing agents. A substantial fraction of GSTP1 tethered interactions represent neo-PPIs that were enriched for splicing factors and nuclear proteins as determined by immunopurification mass spectrometry. LIPT colocalized GSTP1 with serine/arginine repetitive matrix protein 1 (SRRM1), resulting in its redistribution from nuclear speckles to cytoplasmic foci. Cancer cells with enhanced sensitivity to LIPT showed downregulation of metabolic proteins that led to altered lipid metabolism and reduced cell proliferation from GSTP1 molecular glue treatment. Collectively, we show covalent molecular glues of GSTP1 can alter localization of disulfide tethered binding partners and disrupt metabolism in cancer cells.