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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.

A new study has found that large language models (LLMs) like ChatGPT consistently advise women to ask for lower salaries than men.

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The following column by Senator Todd Young (R-Ind.) and Matthew Pottinger, Former Deputy National Security Advisor of the United States, was published in The Washington Post on March 24, 2025. By Sena...

Aldo-keto reductase family 1 member C3 (AKR1C3) is a member of the AKR superfamily of enzymes that metabolize androgen, estrogen, and prostaglandin substrates that drive proliferation in hormone-dependent cancers. Interest in developing selective inhibitors has produced tool compounds for the inactivation or degradation of AKR1C3 with varying degrees of selectivity among the 14 known AKR proteins. Selectivity of AKR1C3 inhibitors across the AKR family is critical since a clinical candidate failed due to hepatotoxicity from off-target inhibition of AKR1D1. Here, we report development of a sulfonyl-triazole (SuTEx) covalent AKR1C3 inhibitor (RJG-2051) that selectively engages a noncatalytic tyrosine residue (Y24) on AKR1C3. Importantly, RJG-2051 exhibited negligible cross-reactivity with AKRs or other proteins across 1800+ tyrosine and lysine sites quantified by chemical proteomics. Our disclosure of a covalent inhibitor for potent AKR1C3 inactivation with proteome-wide selectivity in cells will expedite cell biological studies for testing the therapeutic potential of this metabolic target.

YouTube video by Congressman Don Beyer