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Spotlight on PROTAC: Make "Undruggable” Targets Drugable

2020-06-23
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As researchers continue to explore new drug research and development, in recent years, there have emerged like protein motion (Protein Motion), targeted protein degradation complexes (PROTACs), gene transcription simulation (Transcriptional mimetic), small molecule co-receptor targeting ( SMART) and other emerging drug research and development technologies. As far as the overall development of drug research and development is concerned, both small and large molecule drug forms have their own advantages and disadvantages. At the same time, the PROTAC technology based on the ubiquitination and proteasome system stands out among many new drug research and development technologies and has developed rapidly during the drug discovery process.
PROTAC technical mechanism
PROTAC is a bifunctional specific small molecule, which can be understood as a dumbbell. One end is used to target the target protein that needs to be degraded, and the other end is used to recruit protein degradation systems such as E3 ubiquitinate ligase to bind, and the middle is connected by a suitable linker . A ternary complex consisting of “target protein-PROTAC-E3 ligase and ubiquitin” is formed, so that the target protein and E3 ligase are spatially tightly bound, so that the target protein is ubiquitinated, and then recognized and degraded by the proteasome. This new mechanism can theoretically target all drug target proteins, especially for protein targets previously thought to be non-drugable, using the cell’s own protein destruction mechanism to remove specific oncogenic proteins from the cell, thereby broadening its expansion In the field of drug research, it provides inestimable space and application prospects for the development of new drugs.


PROTACs technology like dumbbells

▲PROTACs technology like dumbbells (Image source: David Parking)


Basic mode of PROTAC technology

▲PROTAC technology basic mode (Photo source: “ACS Chemical Biology”)
PROTAC technology advantages and disadvantages
One of the biggest advantages of PROTACs technology is that it can change the target from “undruggable” to “drugable”. Most small-molecule drugs or monoclonal antibodies require active sites that bind enzymes or receptors to function, however, it is estimated that 80% of proteins in human cells lack such sites. PROTACs can grab the target protein through any corner or gap. Targeting these proteins through PROTACs technology may bring unprecedented breakthroughs in disease treatment.
The protein degrading agent (multicolor) combines a target protein (green) and an E3 ubiquitin ligase (blue) to drive the ubiquitination (purple) and degradation of the target protein based on the proteasome (orange).

protein degrading agent

▲The protein degrading agent (multicolor) combines a target protein (green) and an E3 ubiquitin ligase (blue) to drive the ubiquitination (purple) and degradation of the target protein based on the proteasome (orange). (Source: Arvinas)
To a large extent, PROTAC combines the advantages of small molecule compounds and small molecule nucleic acids, that is, it can effectively target the target protein, and it can also be degraded and cleared. The imagination is very rich. At the same time, PROTAC also has its flaws. For example, the molecule is usually very large, and PK is a major obstacle. Chemical synthesis is also much more difficult, and CMC is also a big challenge.
Off-target toxicity should be one of the most concerned issues in the industry. Traditionally, small molecules, macromolecule drugs, and even small nucleotides that target protein activity generally do not inhibit protein activity completely, nor do they affect the expression of skeleton proteins, which increases the incidence of drug resistance. Probability, but at the same time the residual activity may also guarantee the basic physiological activity of normal cells, tissues and organs, reducing the potential toxicity. As a more complete target degrader, PROTAC, even if the target has been verified before, will it bring more serious toxicity, and it needs to be closely monitored in future clinical trials.
Another hidden danger is that the off-target effect of degradation is not easy to detect and track in preclinical toxicity screening, increasing the risk of later development.

Opportunities and challenges facing PROTAC
PROTAC’s recent breakthroughs in small molecule research have also focused on targetable targets. One of its greatest potential in the future is to target traditional non-targetable targets, such as transcription factors, protein backbone functions, or KRAS mutation, the king of non-drugable targets. Up to 20-30% of tumors contain KRAS mutations, including more than 90% of pancreatic cancer, 50% of colon cancer, and 30% of lung cancer.
At the same time, PROTAC small molecules can not only be used to overcome the resistance of traditional targeted drugs, but also a weapon of combination therapy in the future. The prospect is very worth looking forward to.
PROTAC technology prospects and prospects
As a new technology, PROTACs still have a lot to go in the future. In addition to technological upgrades, in order to move towards the clinic, the scientific and industrial communities need to overcome the drugability problems in various aspects such as PK, PD, bioavailability, and drug delivery methods. The research and development of any kind of drugs needs to be accumulated. Only more solid research and more extensive investment can help PROTACs truly become medicine. At present, PROTAC technology has entered the clinic, and there is no doubt that the future growth is huge and the prospects are broad.

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