Diacylfuroxans Are Masked Nitrile Oxides That Inhibit GPX4 Covalently

GPX4 represents a promising yet difficult-to-drug therapeutic
target
for the treatment of, among others, drug-resistant cancers. Although
most GPX4 inhibitors rely on a chloroacetamide moiety to modify covalently
the protein’s catalytic selenocysteine residue, the discovery
and mechanistic elucidation of structurally diverse GPX4-inhibiting
molecules have uncovered novel electrophilic warheads that bind and
inhibit GPX4. Here, we report our discovery that diacylfuroxans can
act as masked nitrile oxide prodrugs that inhibit GPX4 covalently
with unique cellular and biochemical reactivity compared to existing
classes of GPX4 inhibitors. These observations illuminate a novel
molecular mechanism of action for biologically active furoxans and
also expand the collection of reactive groups capable of targeting
GPX4.