Evidence map›Paper›PMID 32231343›Full record

ArticleNature chemical biology2020

Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles.

John K Eaton, Laura Furst, Richard A Ruberto, Dieter Moosmayer, André Hilpmann, Matthew J Ryan, Katja Zimmermann, Luke L Cai, Michael Niehues, Volker Badock and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 230 papers.

0numbers the graph read from it
0cells of the map it votes in
230citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

230 citing papers in PubMed.

  1. PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators.Journal of enzyme inhibition and medicinal chemistry · 2026
    Review
  2. Article
  3. Article
  4. The Emerging Role of Ferroptosis in Pediatric Cancer Biology and Therapy.International journal of molecular sciences · 2026
    Review
  5. Article
  6. Article
  7. Article
  8. Review
  9. Review
  10. Article
  11. Review
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  14. Article
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  16. Article
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  19. Article
  20. Review

170 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

23 authors.

John K EatonBroad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4633-5546
Laura FurstBroad Institute, Cambridge, MA, USA.
Richard A RubertoBroad Institute, Cambridge, MA, USA.
Dieter MoosmayerBayer AG, Berlin, Germany.
André HilpmannBayer AG, Berlin, Germany.
Matthew J RyanBroad Institute, Cambridge, MA, USA.
Katja ZimmermannBayer AG, Berlin, Germany.
Luke L CaiBroad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4204-1938
Michael NiehuesBayer AG, Berlin, Germany.
Volker BadockBayer AG, Berlin, Germany.
Anneke KrammBroad Institute, Cambridge, MA, USA.
Sixun ChenBroad Institute, Cambridge, MA, USA.
Roman C HilligBayer AG, Berlin, Germany.
Paul A ClemonsBroad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-1800-5112
Stefan GradlBayer AG, Berlin, Germany.
Claire MontagnonBroad Institute, Cambridge, MA, USA.
Kiel E LazarskiBroad Institute, Cambridge, MA, USA.
Sven ChristianBayer AG, Berlin, Germany.
Besnik BajramiBroad Institute, Cambridge, MA, USA.
Roland NeuhausBayer AG, Berlin, Germany.
Ashley L EheimBayer AG, Berlin, Germany.
Vasanthi S ViswanathanBroad Institute, Cambridge, MA, USA. Vasanthi.Sridhar@post.harvard.edu.ORCID http://orcid.org/0000-0001-9878-3629
Stuart L SchreiberBroad Institute, Cambridge, MA, USA. stuart_schreiber@harvard.edu.ORCID http://orcid.org/0000-0003-1922-7558

Funding

SYNTHESIS OF MATERIALS WITH PHYSIOLOGICAL PROPERTIESR01GM038627 · NIGMS · YALE UNIVERSITY · PI SCHREIBER, STUART L · 1987 to 2017
$10.5M
Studies of Materials with Physiological PropertiesR35GM127045 · NIGMS · BROAD INSTITUTE, INC. · PI SCHREIBER, STUART L · 2018 to 2022
$3.2M
NIGMS NIH HHS R01 GM038627NIGMS NIH HHS R35 GM127045
6 · The paper itself

Abstract

We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.

Indexed as

AnimalsCell Line, TumorEnzyme InhibitorsFerroptosisHumansLipid PeroxidationMice, SCIDMolecular ProbesMolecular Targeted TherapyNitrilesOxidesPhospholipid Hydroperoxide Glutathione PeroxidaseProdrugsRats, WistarSelenocysteineSmall Molecule LibrariesEnzyme InhibitorsMolecular ProbesNitrilesOxidesPhospholipid Hydroperoxide Glutathione PeroxidaseProdrugsSelenocysteineSmall Molecule Libraries

Identifiers

PMID32231343
PMCPMC7251976

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.