Engineering ERα degraders with pleiotropic ubiquitin ligase ligands maximizes therapeutic efficacy by co-opting distinct effector ligases
De autoria de Anna Shemorry, Willem den Besten, Melinda M. Mulvihill, Curt J. Essenburg, Nicole Blaquiere, Tracy Kleinheinz, Elisia Villemure, Frank Peale, Gauri Deshmukh, Danilo Maddalo, Elizabeth Levy, Kebing Yu, Elizabeth A. Tovar, Emily Wolfrum, Robert A. Blake, Karthik Nagapudi, William F. Forrest, Steven T. Staben, Carrie R. Graveel, Wayne J. Fairbrother e Ingrid E. Wertz
- Publicado
- Servidor
- bioRxiv
Resumo
Summary
Proximity-inducing compounds that modulate target protein homeostasis are an emerging therapeutic strategy [1]. While the inherent complexity of these bifunctional compounds poses challenges for rational design and bioavailability, their composition also provides opportunities to co-opt specific cellular proteins to maximize therapeutic impact. Here, we systematically evaluate the cellular efficacy, biophysical mechanisms, and therapeutic benefits of a series of bifunctional degrader compounds, that are all engineered with the Estrogen Receptor-alpha (ERα)-inhibitor endoxifen linked to different bioactive ubiquitin ligase ligands. Bifunctional ERα degraders that incorporate CRL4-CRBN-binding ligands promoted the most potent ERα degradation, whereas those incorporating either CRL2-VHL- or IAP-binding ligands maximized the depth of ERα degradation. Notably, ERα degraders containing pan-IAP antagonist ligands significantly decreased the proliferation of ERα-dependent cells relative to clinical-stage ERα-degraders, including the SERDs fulvestrant and GDC-9545 and the bifunctional degrader ARV-471. Mechanistic studies revealed that pan-IAP antagonist-based ERα degraders uniquely promote TNFα-dependent cell death, unlike the clinical-stage comparators. Remarkably, the pan-IAP antagonist-ERα-degraders co-opt distinct effector ligases to achieve dual therapeutic effects: they harness XIAP within tumor cells to promote ERα degradation, and activate cIAP1/2 within tumor and immune cells to induce TNFα that drives tumor cell death. Our studies demonstrate a broader concept that co-opting the discrete functions of a selected set of cellular effectors, while simultaneously modulating therapeutic target protein homeostasis, are dual strategies that can be leveraged to maximize the efficacy of induced proximity therapeutics.
Ler o preprint