AI Article Synopsis
- - TPD can effectively eliminate disease-causing proteins by engaging a cell’s protein degradation system, overcoming limitations of traditional inhibitors that typically target only one mechanism.
- - The CYpHER technology utilizes a pH-dependent release system and a rapidly cycling transferrin receptor to enhance the delivery of therapeutic agents to surface and extracellular targets, increasing treatment potency while potentially reducing side effects.
- - Successful application of CYpHER was demonstrated both in laboratory settings (in vitro) with specific cancer markers (EGFR and PD-L1) and in animal studies (in vivo) using a model of lung cancer driven by EGFR.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464628 | PMC |
| http://dx.doi.org/10.1038/s41467-024-52975-2 | DOI Listing |
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Article Synopsis
- - TPD can effectively eliminate disease-causing proteins by engaging a cell’s protein degradation system, overcoming limitations of traditional inhibitors that typically target only one mechanism.
- - The CYpHER technology utilizes a pH-dependent release system and a rapidly cycling transferrin receptor to enhance the delivery of therapeutic agents to surface and extracellular targets, increasing treatment potency while potentially reducing side effects.
- - Successful application of CYpHER was demonstrated both in laboratory settings (in vitro) with specific cancer markers (EGFR and PD-L1) and in animal studies (in vivo) using a model of lung cancer driven by EGFR.
CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect.
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