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

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

  • Nat Commun. 2025 Dec 11;16(1):11445. doi: 10.1038/s41467-025-66382-8.
Jin Du 1,  Elisia Villemure # 2,  Matthew Johnson # 3,  Caleigh Azumaya 3,  Catarina J Gaspar 1,  Scot Marsters 1,  David Lawrence 1,  Scott Foster 1,  Alexis Rohou 3,  Tommy K Cheung 4,  Christopher M Rose 4,  Thomas Garner 5,  Soo Ro 5,  Kevin Clark 5,  Maureen H Beresini 5,  Marie-Gabrielle Braun 2,  Joachim Rudolph 6,  Peter Hsu 7,  Avi Ashkenazi 8
Affiliations

Affiliations

  • 1 Department of Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
  • 2 Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA.
  • 3 Department of Structural Biology, Genentech, Inc., South San Francisco, CA, USA.
  • 4 Department of Proteomic and Genomic Technologies, Genentech, Inc., South San Francisco, CA, USA.
  • 5 Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
  • 6 Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA. [email protected].
  • 7 Department of Structural Biology, Genentech, Inc., South San Francisco, CA, USA. [email protected].
  • 8 Department of Research Oncology, Genentech, Inc., South San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 41381506 DOI: 10.1038/s41467-025-66382-8
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.

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