Evidence map›Paper›PMID 40539767›Full record

ArticleACS chemical biology2025

Discovery and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1.

Lior Soday, Chotima Seripracharat, Janine L Gray, André F S Luz, Ryan T Howard, Ravi Singh, Thomas J Burden, Erika Bernardini, Miguel Mateus-Pinheiro, Jens Petersen and 16 more

Abstract read
In one paragraph

Article in ACS chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

26 authors.

Lior SodayDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.
Chotima SeripracharatDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.
Janine L GrayDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.ORCID 0000-0001-8679-2499
André F S LuzResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon 1649-004, Portugal.
Ryan T HowardDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.
Ravi SinghDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.ORCID 0000-0003-4344-4085
Thomas J BurdenDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.ORCID 0000-0001-9418-686X
Erika BernardiniDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.
Miguel Mateus-PinheiroResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon 1649-004, Portugal.
Jens PetersenDiscovery Sciences, R&D Gothenburg, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Anders GunnarssonDiscovery Sciences, R&D Gothenburg, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Jenny GunnarssonDiscovery Sciences, R&D Gothenburg, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Anna AagaardDiscovery Sciences, R&D Gothenburg, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Tove SjögrenDiscovery Sciences, R&D Gothenburg, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.ORCID 0000-0002-6703-4200
Sarah MaslenThe Francis Crick Institute, London NW1 1AT, U.K.
Edward J BartlettDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.
Abigail F IlesDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.
David M SmithHit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
James S ScottHit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.ORCID 0000-0002-2263-7024
Mark SkehelThe Francis Crick Institute, London NW1 1AT, U.K.
Andrew M DavisHit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Ana S RessurreiçãoResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon 1649-004, Portugal.
Rui MoreiraResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon 1649-004, Portugal.
Cecília M P RodriguesResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon 1649-004, Portugal.
Avinash R ShenoyDepartment of Infectious Diseases, Imperial College London, Flowers Building, South Kensington Campus, London SW7 2AZ, U.K.
Edward W TateDepartment of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.ORCID 0000-0003-2213-5814

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated

Indexed as

Drug DiscoveryNecroptosisProtein Kinase InhibitorsReceptor-Interacting Protein Serine-Threonine KinasesAnimalsCrystallography, X-RayHigh-Throughput Screening AssaysHumansMiceProtein Kinase InhibitorsReceptor-Interacting Protein Serine-Threonine KinasesRIPK1 protein, human

Identifiers

PMID40539767
PMCPMC12281487

What OpenQuestion holds

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Registered trials

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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.