Structure–activity relationships of GPX4 inhibitor warheads

doi:10.1016/j.bmcl.2020.127538

Bioorganic & Medicinal Chemistry Letters

Volume 30, Issue 23, 1 December 2020, 127538

https://doi.org/10.1016/j.bmcl.2020.127538 Get rights and content

Abstract

Direct inhibition of GPX4 requires covalent modification of the active-site selenocysteine. While phenotypic screening has revealed that activated alkyl chlorides and masked nitrile oxides can inhibit GPX4 covalently, a systematic assessment of potential electrophilic warheads with the capacity to inhibit cellular GPX4 has been lacking. Here, we survey more than 25 electrophilic warheads across several distinct GPX4-targeting scaffolds. We find that electrophiles with attenuated reactivity compared to chloroacetamides are unable to inhibit GPX4 despite the expected nucleophilicity of the selenocysteine residue. However, highly reactive propiolamides we uncover in this study can substitute for chloroacetamide and nitroisoxazole warheads in GPX4 inhibitors. Our observations suggest that electrophile masking strategies, including those we describe for propiolamide- and nitrile-oxide-based warheads, may be promising for the development of improved covalent GPX4 inhibitors.

Section snippets

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.L.S. serves on the Board of Directors of the Genomics Institute of the Novartis Research Foundation (“GNF”); is a shareholder and serves on the Board of Directors of Jnana Therapeutics; is a shareholder of Forma Therapeutics; is a shareholder and advises Kojin Therapeutics, Kisbee Therapeutics, Decibel Therapeutics and Eikonizo Therapeutics; serves on the

Acknowledgements

This work was supported by grants from the National Institutes of Health (R01GM038627 and R35GM127045). We thank Bogdan Budnik and Renee Robinson of the Harvard Center for Mass Spectrometry for assistance with proteomics.

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Structure–activity relationships of GPX4 inhibitor warheads

Abstract

Section snippets

Declaration of Competing Interest

Acknowledgements

Cell

Cell

Cell

Biochim Biophys Acta – Mol Cell Biol Lipids

Chem Biol

Bioorganic Med Chem Lett

Biochem Biophys Res Commun

J Biol Chem

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway

Nature

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

Nature

Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress

Cancer Cell

Structural basis for catalytic activity and enzyme polymerization of phospholipid

Biochemistry

2-Chloropropionamide as a low-reactivity electrophile for irreversible small-molecule probe identification

ACS Chem Biol

Selective covalent targeting of GPX4 Using masked nitrile-oxide electrophiles

Nat Chem Biol

Diacylfuroxans are masked nitrile oxides that inhibit GPX4 covalently

J Am Chem Soc

Selective and reversible modification of kinase cysteines with chlorofluoroacetamides

Nat Chem Biol