ArticleCommunications biology2024
Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC.
Article in Communications biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Resistance to doxorubicin therapy in breast cancer cells could be attenuated by ligustilide: impact on autophagy and LncRNA H19.BMC complementary medicine and therapies · 2026Article
- SCaN: A Screening and Characterization Platform for Nanosuspensions Enables In Vivo Delivery of a Crystalline hRpn13ACS pharmacology & translational science · 2026Article
- Unhooking the Hook: Optimization of the Aurora A Targeting PROTACJournal of medicinal chemistry · 2026Article
- Cell line-specific estrogen responses uncover functional sex differences in murine macrophages.Biology of sex differences · 2025Article
- Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors.Journal of medicinal chemistry · 2025Article
- Rational Design of PROTAC Linkers Featuring Ferrocene as a Molecular Hinge to Enable Dynamic Conformational Changes.Journal of the American Chemical Society · 2025Article
- Property-based optimisation of PROTACs.RSC medicinal chemistry · 2025Article
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Authors and funding
36 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.
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Registered trials
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.