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Small Molecule Allosteric inhibitors of GPX4

ABSTRACT: Encouraged by the dependence of drug-resistant, metastatic cancers on GPX4, we examined biophysical mechanisms of GPX4 inhibition, which revealed an unexpected allosteric binding site. We found that this site was involved in native modulation of GPX4 activity. Binding of inhibitors to this allosteric site caused a conformational change, inhibition of activity, and subsequent cellular GPX4 protein degradation. To verify this binding site in an unbiased manner, we screened a library of compounds, and identified and validated that a novel additional compound can bind in this allosteric site, inhibiting and degrading GPX4. We determined co-crystal structures of six different inhibitors bound in this site. We have thus discovered a new allosteric mechanism for small molecules targeting aggressive cancers dependent on GPX4.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Brent R. Stockwell

PROVIDER: MSV000090526 | MassIVE | Wed Oct 12 18:43:00 BST 2022

REPOSITORIES: MassIVE

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