PROTAC is a novel technique that induces targeted protein degradation by the ubiquitin-proteasome system (UPS). Different from the traditional occupation-driven pharmacological principles, event-driven PROTAC technology has many advantages, such as high activity, high selectivity, catalytic degradation mode, and targeting non-proprietary drug targets.
1. The mechanism of action of PROTAC
PPROTAC (proteolysis targeting chimera) is also called protein targeted degradation chimera. Its molecule is bispecific and consists of three parts, a binding ligand on one end that binds to ubiquitin ligase E3 and Protein of Interest (POI) on the other end, and a linker connecting the two ligands in the middle.
In natural biological reactions, ubiquitin modification involves a series of reactions of ubiquitin-activating enzyme E1, binding enzyme E2, and ubiquitin ligase E3. Based on the energy of ATP, ubiquitin activase E1 activates ubiquitin, then transfers it to ubiquitin binding enzyme E2 and connects to the Cys of the active site of E2 through thioester bond. E2 can transfer ubiquitin directly to the Lys residue of the target protein, but the ubiquitin ligase E3 is needed for ubiquitin conversion of the target protein. E3 ubiquitin ligase is specific, which can recognize a specific target protein on one end, locate E2 on the other end, and then put a ubiquitin “tag” on the target protein. The target protein is recognized and degraded by proteasome when more than one ubiquitin is labeled. This system exists widely in all pathways of life and can well regulate the level of proteins.
With the above reactions, PROTAC can successfully hijack ubiquitin ligase E3, which can label the target protein with “death” through its terminal-specific ubiquitin ligase E3 ligand. When the other end of the PROTAC molecule binds to the target protein, the two molecules can be pulled closer together in space to form a ternary complex that can ubiquitinate the target protein through a series of reactions. When the target protein is ubiquitinated many times, it can be recognized by the proteosome in the human body, which is degraded into polypeptide fragments and becomes completely inactive. Interestingly, the PROTAC molecule will not be degraded, but will join the next “hijacking”.
2. Advantages of PROTAC development
Compared with traditional small molecular drugs, PROTAC is young, which does not attack the pathogenic protein directly, but interferes and degrades the pathogenic protein by mobilizing the natural resources in the human body. Compared with traditional small molecular inhibitors, PROTAC molecules have certain advantages in dosage, and they can be recycled repeatedly to exert their efficacy, just like the common catalysts in chemical reactions, so the amount of catalyst is sufficient in theory. It is expected to reduce the dose and concentration and is safer.
Traditional small molecular drugs only act on target proteins with clear active sites, such as enzymes, which inhibit the target by binding to their active sites. The desired effect cannot be achieved under this MOA in many cases. For example, there are pathogenic proteins that don’t function under enzymes, such as translation and transcription proteins, and cell scaffold proteins. In addition, when the target protein is overexpressed, other competitive ligands are overexpressed, or when the active site of the target protein is mutated, traditional small molecule inhibitors won’ work.
The morphology of these proteins is conventionally considered to be “undruggable” targets, but PROTAC molecules can overcome these limitations.
3. The prospects of PROTAC
The emergence of PROTAC opened a brand new world for the development of new molecular drugs. First, PROTAC is of great potential as there are more than 600 kinds of ubiquitin ligase E3 in human body, and only a few of them are utilized at present. Second, PROTAC has a short history that only a few molecules have entered clinical research by now, such as ARV-110 and ARV-471, but no products have been approved. Many innovators and entrepreneurs in the biomedical industry are expecting to make a completely new start in this brand-new track, with many companies increasing their R&D investment in PROTAC currently, hoping to overtake at the next turning point.
Creative Biolabs has established a professional PROTAC platform to provide strong technical support for innovative partners based on experience and technology in PROTAC.