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Diacylfuroxans Are Masked Nitrile Oxides That Inhibit GPX4 Covalently

preprint
submitted on 23.01.2019, 05:46 and posted on 23.01.2019, 16:34 by John Eaton, Richard A. Ruberto, Anneke Kramm, Vasanthi S. Viswanathan, Stuart Schreiber

GPX4 represents a promising yet difficult-to-drug therapeutic target for the treatment of, among others, drug-resistant cancers. While 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 has uncovered novel electrophilic warheads that bind and inhibit GPX4. Here we report our discovery that diacylfuroxans can act as masked nitrile oxides that inhibit GPX4 covalently. These observations illuminate a novel molecular mechanism of action for biologically active furoxans and also suggest that nitrile oxides may be uniquely suited to targeting GPX4.

Funding

Studies of Materials with Physiological Properties

National Institute of General Medical Sciences

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Studies of Materials with Physiological Properties

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

jeaton@broadinstitute.org

Institution

Broad Institute

Country

United States

ORCID For Submitting Author

0000-0003-4633-5546

Declaration of Conflict of Interest

S.L.S. is a member of the Board of Directors of the Genomics Institute of the Novartis Research Foundation (“GNF”); a shareholder and member of the Board of Directors of Jnana Therapeutics; a shareholder of Forma Therapeutics; a shareholder of and adviser to Decibel Therapeutics and Eikonizo Therapeutics; an adviser to Eisai, Inc., the Ono Pharma Foundation, and F-Prime Capital Partners; and a Novartis Faculty Scholar.

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v1 - Original Submission

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