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
  • 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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