ArticleJournal of the American Chemical Society2025
Rational Design of PROTAC Linkers Featuring Ferrocene as a Molecular Hinge to Enable Dynamic Conformational Changes.
Article in Journal of the American Chemical Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems.Acta pharmacologica Sinica · 2026Review
- Delivering Degradation: Nanomedicine and Programmable Proximity Platforms for Targeted Protein Degradation.Pharmaceutics · 2026Review
- From Ternary Modeling to Predictive PROTAC Design: A Computational Perspective.Journal of chemical information and modeling · 2026Article
- Targeted protein degradation: bridging chemical biology and clinical translation.Acta pharmacologica Sinica · 2026Review
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Proteolysis-targeting chimera (PROTAC) in cancer: design principles and applications on "undruggable" targets.Biomarker research · 2026Review
- RuPHOTACs Provide Photocontrol Over Protein Degradation with Optimized Properties for Biological Applications.Research square · 2026Article
- A Gold-PROTAC Degrades the Oncogenic Tyrosine Kinase MERTK: Insights into the Degradome from a Steady-State System.ACS chemical biology · 2026Article
- Comparative Study of Ferrocene- and Indene-Based Tamoxifen Derivatives of Different Molecular Flexibility on High-Mortality Cancer Cell Lines.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Recent Advances in the Development of Pro-PROTAC for Selective Protein Degradation.Pharmaceutics · 2025Review
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and degradation of a target protein via recruitment to an E3 ligase. The linker influences many steps of the PROTAC mode of action, from cellular permeability to ternary complex formation and target degradation. Much interest has therefore been devoted to linker design to fine-tune molecular and mechanistic properties of PROTACs. In this study, we present FerroTACs, a novel PROTAC design strategy incorporating ferrocene as the linker chemotype. We exemplify the approach across three different PROTAC systems: VHL-VHL (homo-PROTACs), VHL-CRBN, and VHL-BETs. We find that ferrocene's unique organometallic structure, featuring freely rotating cyclopentadienyl rings around a central Fe(II) ion, acts as a molecular hinge enabling structural adjustment to the environment that results in properties alteration, i.e., chameleonicity. Conformational analyses via NMR spectroscopy support ferrocene's role in fostering intramolecular interactions that result in a more folded state in an apolar environment. This property promotes compact conformations, improving cellular permeability and reducing efflux liabilities. Cellular assays demonstrate that FerroTACs exhibit robust target degradation and cell permeability profiles, en-par or enhanced compared to benchmark PROTACs
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