Evidence map›Paper›PMID 41381506›Full record

ArticleNature communications2025

Chemically-induced degradation of the endoplasmic-reticulum stress sensor IRE1 by a VHL-recruiting chimera.

Jin Du, Elisia Villemure, Matthew Johnson, Caleigh Azumaya, Catarina J Gaspar, Scot Marsters, David Lawrence, Scott Foster, Alexis Rohou, Tommy K Cheung and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. A Two-Level, Multidimensional Framework for Understanding and Treating Clinician Fatigue.Health care analysis : HCA : journal of health philosophy and policy · 2026
    Article
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

19 authors.

Jin DuDepartment of Research Oncology, Genentech, Inc., South San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-8224-250X
Elisia Villemure *Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA.
Matthew Johnson *Department of Structural Biology, Genentech, Inc., South San Francisco, CA, USA.
Caleigh AzumayaDepartment of Structural Biology, Genentech, Inc., South San Francisco, CA, USA.
Catarina J GasparDepartment of Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
Scot MarstersDepartment of Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
David LawrenceDepartment of Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
Scott FosterDepartment of Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
Alexis RohouDepartment of Structural Biology, Genentech, Inc., South San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-3343-9621
Tommy K CheungDepartment of Proteomic and Genomic Technologies, Genentech, Inc., South San Francisco, CA, USA.
Christopher M RoseDepartment of Proteomic and Genomic Technologies, Genentech, Inc., South San Francisco, CA, USA.
Thomas GarnerDepartment of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
Soo RoDepartment of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
Kevin ClarkDepartment of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
Maureen H BeresiniDepartment of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
Marie-Gabrielle BraunDepartment of Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA.
Joachim RudolphDepartment of Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA. joachimr@gene.com.ORCID http://orcid.org/0000-0002-0806-6106
Peter HsuDepartment of Structural Biology, Genentech, Inc., South San Francisco, CA, USA. hsup2@gene.com.ORCID http://orcid.org/0000-0002-9381-6564
Avi AshkenaziDepartment of Research Oncology, Genentech, Inc., South San Francisco, CA, USA. aa@gene.com.ORCID http://orcid.org/0000-0002-6890-4589

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-endoribonuclease and scaffolding activities. Cancer cells often co-opt IRE1 to facilitate growth. An IRE1-RNase inhibitor has entered clinical trials; however, recent work uncovered a significant nonenzymatic IRE1 dependency in cancer. To fully disrupt IRE1, we describe a proteolysis-targeting chimera (G6374) that couples an IRE1-kinase ligand to a compound that binds the ubiquitin Cullin-RING Ligase (CRL) substrate receptor, VHL. G6374 induces a stable, cooperative interaction between IRE1 and VHL, driving K48-linked ubiquitination on two principal lysine residues in the IRE1-kinase domain and inducing proteasomal IRE1 degradation. Cryogenic electron microscopy and mutagenesis studies reveal a 2:2 IRE1:VHL ternary-complex topology and critical interactional features, informing future designs. G6374 blocks growth of IRE1-dependent cancer cells irrespective of their dependency mode, while sparing IRE1-independent cells. We provide a proof-of-concept for VHL-based degradation of an ER-transmembrane protein, advancing strategies to fully disrupt IRE1.

Indexed as

Endoplasmic Reticulum StressEndoribonucleasesProtein Serine-Threonine KinasesVon Hippel-Lindau Tumor Suppressor ProteinCell Line, TumorHEK293 CellsHumansProteolysisUbiquitinationEndoribonucleasesERN1 protein, humanProtein Serine-Threonine KinasesVHL protein, humanVon Hippel-Lindau Tumor Suppressor Protein

Identifiers

PMID41381506
PMCPMC12749748

What OpenQuestion holds

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LicenceCC BY
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.