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The latest research progress of protein degradation agents: 29 effective individuals and 7 future opportunities
Protein degradation agents: 29 effective individuals and 7 future opportunities. The human proteome contains about 20,000 proteins, of which more than 600 are estimated to have important functions for various types of cancer, including nearly 400 non-enzymatic proteins, which are difficult to target by traditional pharmacology.
The latest developments in Targeted protein degradation (TPD), including molecular glues and bifunctional degradation agents, and proteolytic targeting chimeras (PROTACs) have made it possible to target non-druggable proteins.
PROTACs form a ternary complex with the hijacked E3 ubiquitin ligase and target protein, leading to polyubiquitination and degradation of the target protein. Of the approximately 600 human E3 ligases, most have not been discovered, which provides a huge opportunity for the development of tissue, tumor and subcellular selective degradants that target oncoproteins.
Since the PROTAC concept was first published in 2001, some important breakthroughs in this field have led PROTAC to become the hottest new field of drug research and development. In the past 5 years, the TPD field has seen explosive growth, and two PROTACs entered the clinical development stage as anti-tumor drugs in 2019.
PROTAC technology timeline:
Ubiquitination degradation process:
E3 ubiquitin ligase classification, including HECT, RING and RBR, etc.:
E3 enzyme ligand for protein degradation:
The basic structure of PROTAC molecule:
PROTAC molecule induces the formation of a ternary complex of target protein-small molecule-E3 enzyme:
The structure of several types of representative PROTAC molecules:
The tissue selective expression of E3 enzyme is of great significance to the degradation activity of PROTAC:
The currently reported degradants that are effective on tumors in vivo are as follows (29):
With the development of the first small molecule degradation agent based on CRBN and VHL ligands in 2015, the rate of PROTAC drug development has increased exponentially.
At present, many new effective degradants in vivo have been developed, and new substrates of CRBN, molecular glue and other E3 ligands have also been discovered. Two PROTACs have entered the clinical research and development stage.
Looking ahead, there are at least seven major opportunities in the field of targeted protein degradation (TPD):
1) Develop degradants that target “undruggable” targets such as transcription factors that lack enzyme active sites;
2) Develop new small molecule ligands for E3 enzyme;
3) Develop subtype selective degradation agents;
4) Develop selective degradation agents for mutant proteins.
5) Based on the differential expression level of E3 ligase in tumor and normal cells, develop special PROTACs to reduce side effects and improve treatment window;
6) Develop effective degradants in vivo based on hydrophobic tags;
7) With the analysis of more POI-PROTAC-E3 ternary composite structures, it is expected to usher in a reasonable design of PROTAC based on the structure.
(source:internet, reference only)