What are the new development trends in the direction of protein degradation agents in the past year?

A small number of protein degradation agents have reached the clinical stage, and as new molecules and mechanisms continue to be discovered, more new pipelines will emerge.
so far, protein degradation agents have focused on cancer treatment because there are usually obvious targets in cancer cells, and protein degradation agents can eventually be used in other diseases, such as diseases of the central nervous system.
a while ago, the Genetic Engineering and Biotechnology News website published an article on TargetEd Protein Destruction: Advances in PROTACs Other Degraders, which take stock of new trends in protein degradation agents over the past year.
1. Development/optimization of new degradation molecule PROTAC (protein-targeted degradation bind) protein degradation agents uses the body's natural protein recovery system to degrade disease-causing proteins.
PROTAC protein degradors recruit E3 connective enzymes, label target proteins with ubibin, and guide them to degradation by proteases.
after the target protein is degraded, the PROTAC protein degradation agent is released and can be re-used to degrade other target proteins.
PROTAC is now a track of opportunities and challenges.
represented by C4 Therapeutics, companies are committed to the development and optimization of innovative protein degradation agents.
C4 Therapeutics mainly covers two protein degradation agents: the first class, called MonoDACs, is a single-function degradation biolytic compound, also known as a "molecular glue."
can enhance the binding of E3 connective enzymes to target proteins by binding to E3 connective enzymes and forming new regions on E3 connective enzymes.
Class II, called BidaCs, is a dual-functional degradation biolytic compound, also known as a "heterogeneic biodegrader", in which one end of the molecule binds to the pathogenic target protein and the other end binds to the E3 connective enzyme.
the vast majority of PROTACs currently fall within the scope of BidaCs.
" tends to have smaller molecules than BiDAC, which has an advantage in simplifying the development process.
, MonoDAC relies more on protein interactions, making their range of target proteins relatively narrow.
," Dr. Stewart Fisher, C4 Therapeutics' chief scientific officer, said in the article.
2. There are two types of E3 connective enzymes commonly used in protein degradation therapy, cereblon and VHL connective enzymes.
, however, certain cancer cells can reduce the expression levels of cereblon and VHL connective enzymes and reduce the efficacy of protein degradation agents.
addition, certain proteins cannot be degraded by cereblon and VHL connective enzymes.
, it is necessary to develop E3 connective enzymes other than cereblon and VHL connective enzymes.
October 2020, Cullgen published an article in the journal Pharmaceutical Chemistry, Journal of Medicinal Chemistry, about the discovery of candidates for TRK selective protein degradation agents.
TRK is known as the neurotrophic factor subject tyrosine kinase, and the fusion protein produced by the TRK mutation has been found to be found in a wide range of human malignancies, including lung cancer, colorectal cancer and soft tissue sarcoma.
article, Cullgen developed two new TRK-targeted protein degradation agents: CG416 and CG428, designed to address side effects and drug resistance in patients taking TRK inhibitors.
3. Improving bit accuracy Develops other E3 connective enzymes besides cereblon and VHL connective enzymes, and can also extend the range of PROTAC targeting bits.
, for example, when the target protein is a membrane protein, the use of the targeted membrane protein E3 connective enzyme is better than the use of E3 connective enzyme located in the nuclea of the cell.
Progenra is trying this, using its proprietary platform, UbiPro, to discover a range of E3 connective enzymes and de-ubigenases (another set of enzymes in UPS).
one of its research products can target K-Ras, a common membrane protein target in cancer.
4. Bypassing the E3 connective enzyme system using a specific E3 connective enzyme limits the selection of the target protein, and Amphista Therapeutics takes a different approach.
, chief scientific officer of the company, said in the article:
If the substrate is close enough to the ubiganism protease system and close enough to last long enough, the substrate will also degrade."
thy is the strategy we use."
Amphista has designed multiple "magnet" ligations that recruit multiple UPS proteins and activate multiple parallel degradation pathways.
this approach makes cancer less resistant.
is currently using these new mechanisms to develop two types of small molecule drugs: one that recruits desulbinases and the other that recruits proteases directly.
amphista plans to conduct its first clinical trial in 2023.
o we look forward to the near future, in this new track, new protein degradation agents can continue to emerge, more new drugs come out, for the vast number of patients to bring the gospel."
: s1. Targeted Protein Destruction: Advances in PROTACs Other Degraders. Retrieved Jan 4, 2021, from