Related Experiment Video

Updated: Jun 11, 2025

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
05:33

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

9.5K

CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect

Zachary R Crook1,2,3, Gregory P Sevilla1,2,3, Pamela Young2

  • 1Cyclera Therapeutics Inc, Seattle, WA, 98115, USA.

Nature Communications
|October 9, 2024
PubMed

Insights

CYpHER technology offers a novel approach to targeted protein degradation by utilizing pH-dependent endolysosomal delivery and recycling. This method enhances potency and reduces off-target risks for treating diseases driven by multiple protein functions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Conventional inhibitors often fail to address multiple pathogenic mechanisms of disease-causing proteins.
  • Targeted protein degradation (TPD) offers a strategy to eliminate proteins and all their functions.
  • Existing TPD strategies involve E3 ligases or endolysosomal pathway uptake.

Purpose of the Study:

  • To introduce CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology for targeted protein degradation.
  • To leverage a catalytic mechanism with the specificity and modular design of endolysosomal uptake.
  • To enhance drug potency and reduce off-target tissue exposure risks.

Main Methods:

  • CYpHER utilizes pH-dependent release of the target engager.
  • The transferrin receptor (TfR) serves as the uptake receptor for rapid cycling.
  • Demonstrated in vitro for EGFR and PD-L1, and in vivo for EGFR in non-small cell lung cancer models.

Main Results:

  • CYpHER induces endolysosomal delivery of surface and extracellular targets.
  • The technology allows for drug re-use, potentially increasing potency.
  • TfR-based targeting enables application in tumors overexpressing TfR and potential CNS transport.

Conclusions:

  • CYpHER technology provides a potent and durable TPD strategy.
  • The approach combines catalytic efficiency with endolysosomal uptake advantages.
  • This method shows promise for treating EGFR-driven cancers and other TfR-targeted diseases.

More Related Videos

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.1K
Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes07:22

Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes

Published on: January 12, 2024

3.3K

Related Concept Videos

The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
8.5K
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.2K
The Proteasome Structure01:17

The Proteasome Structure

The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
712
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.5K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.5K
Role of Matrix Metalloproteases in Degradation of ECM01:23

Role of Matrix Metalloproteases in Degradation of ECM

Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult...
2.3K