ArticleNature communications2024
CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
12 citing papers in PubMed.
- Article
- TROP2-Targeting Chimeras (TRTACs) for Tumor Cell-Selective Membrane Protein Degradation and Enhanced Drug Delivery.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Macropinocytosis-mediated recyclable LYTACs (McR-TACs) for receptor-independent protein degradation.Nature biotechnology · 2026Article
- Synergistic Remodeling of Tumor Immune Microenvironment via a DNA Nanodevice Integrating STING Activation and Lysosome-Targeted PD-L1 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Transferrin receptor 1: an emerging therapeutic target in cancer beyond iron metabolism.Cancer cell international · 2026Review
- Multispecific nanobody degraders co-deplete membrane receptors and enable targeted delivery of diverse payloads.bioRxiv : the preprint server for biology · 2026Article
- Dynamic reprogramming of the tumor immune network via multicycle checkpoint degradation for cancer immunotherapy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Bioengineered ferritin-based lysosome-targeting chimera platform for tumor-targeted therapy.Nature communications · 2026Article
- Polymeric Lysosome-Targeting Chimeras (PolyTACs): Extracellular Targeted Protein Degradation without Co-Opting Lysosome-Targeting Receptors.Journal of the American Chemical Society · 2026Article
- Computational design of pH-sensitive binders.bioRxiv : the preprint server for biology · 2025Article
- Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs.Journal of hematology & oncology · 2025Review
Corrections and comments
- Update of
Authors and funding
9 authors.
Funding
Abstract
Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.
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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 Socratic graph.