Engineering ERα degraders with pleiotropic ubiquitin ligase ligands maximizes therapeutic efficacy by co-opting distinct effector ligases

  • Cell Chem Biol. 2025 May 15;32(5):694-709.e35. doi: 10.1016/j.chembiol.2025.04.008.
Anna Shemorry  1 ,  Willem den Besten  1 ,  Melinda M Mulvihill  2 ,  Curt J Essenburg  3 ,  Nicole Blaquiere  4 ,  Tracy Kleinheinz  2 ,  Elisia Villemure  4 ,  Frank Peale  5 ,  Gauri Deshmukh  6 ,  Danilo Maddalo  7 ,  Elizabeth Levy  8 ,  Kebing Yu  9 ,  Matthew R Steensma  3 ,  Elizabeth A Tovar  3 ,  Emily Wolfrum  10 ,  Karthik Nagapudi  8 ,  Robert A Blake  2 ,  William F Forrest  11 ,  Steven T Staben  4 ,  Carrie R Graveel  3 ,  Wayne J Fairbrother  12 ,  Ingrid E Wertz  13
Affiliations
  • 1. Discovery Oncology, Genentech, South San Francisco, CA 94080, USA; Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA.
  • 2. Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA.
  • 3. Department of Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
  • 4. Department of Discovery Chemistry, Genentech, South San Francisco, CA 94080, USA.
  • 5. Department of Research Pathology, Genentech, South San Francisco, CA, USA.
  • 6. DMPK, Genentech, South San Francisco, CA 94080, USA.
  • 7. Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
  • 8. Department of Small Molecule Pharmaceutical Sciences, Genentech, South San Francisco, CA 94080, USA.
  • 9. Microchemistry Proteomics and Lipidomics, Genentech, South San Francisco, CA 94080, USA.
  • 10. Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
  • 11. OMNI Bioinformatics, Genentech, South San Francisco, CA 94080, USA.
  • 12. Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address: [email protected].
  • 13. Discovery Oncology, Genentech, South San Francisco, CA 94080, USA; Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address: [email protected].
PMID: 40378821 DOI: 10.1016/j.chembiol.2025.04.008
Abstract

Proximity-inducing compounds that modulate target protein homeostasis represent an emerging therapeutic strategy. While the inherent complexity of these bifunctional compounds presents certain challenges, their unique composition offers opportunities to co-opt specific cellular effectors to enhance therapeutic impact. In this study, we systematically evaluate a series of bifunctional degrader compounds engineered with the estrogen receptor-alpha (ERα) inhibitor endoxifen linked to various bioactive ubiquitin Ligase ligands. Notably, ERα degraders containing pan-IAP antagonist ligands significantly reduced the proliferation of ERα-dependent cells compared to clinical-stage ERα degraders. These pan-IAP antagonist-based ERα degraders leverage distinct effector ligases to achieve dual therapeutic effects: They utilize XIAP within tumor cells to promote ERα degradation and activate cIAP1/2 in both tumor and immune cells to induce TNFα, which drives tumor cell death. Our findings illustrate a broader concept that co-opting the discrete functions of selected cellular effectors, while simultaneously modulating therapeutic target protein homeostasis, are dual strategies that can significantly enhance the efficacy of induced proximity therapeutics.

Keywords
ERα degraders; TNFα; XIAP; cIAP1/2; chemical biology; degrader efficacy; induced proximity; pleiotropic ligands; tumor cell death.
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