Novel Therapies of Protein Degradation Represented by PROTAC

An important method for cells to regulate their internal protein concentration is through the Ubiquitin/Proteasome system (UPS) that connects the ubiquitinase to the target protein through a complex protein system, and then the proteasome recognizes the ubiquitinase to find the target protein and degrade it. The key step is the transfer of ubiquitinase from E3 ligase to the target protein, under the premise that the E3 ligase and the target protein are close enough.

Small molecule drugs that use the UPS system to degrade the target protein are already approved by the FDA. Although these drugs are not designed based on the UPS system, they act by promoting the UPS system to degrade the target protein. Fulvestrant and Pomalidomide are typical representatives. Using small molecules to promote the targeted degradation of the target protein by the UPS system is feasible.

When it comes to targeted protein degradation technology, Protac is undoubtedly a hot topic in recent years, which can effectively degrade the targets that are "invisible" for traditional small molecule inhibitors, greatly expanding the prospects of tumors and other refractory diseases therapy. Theoretically, PROTAC technology has the following advantages.

• PROTAC molecules have catalytic degradation function. Unlike a small molecule inhibitor, a single PROTAC molecule can degrade multiple protein molecules. And as long as there are PROTAC molecules in the cells, the efficacy can be maintained.
• It is unnecessary for PROTAC to act on the active site of the protein to inhibit its activity. PROTAC may act on some traditionally non-drugable targets.

As PROTAC takes effect by degrading the disease-causing protein, when the resistance of small molecules is caused by the synthesis of more disease-causing proteins, PROTAC is not subject to such drug resistance. All in all, PROTAC technology has the combined strengths of small-molecule chemicals, large-molecule biopharmaceuticals, and RNAi molecules, and may become a key technology for the next batch of blockbuster drugs.

In addition to PROTAC, other protein degradation technologies are evolving like LYTAC, AUTAC, and ATTEC, which, compared with PROTAC, are slightly immature, but in time they may forge radical new ground in innovative drugs.

An LYTAC (Lysosomal Targeting Chimera) molecule is composed of an antibody or small molecule connected by a long chain (linker) to multiple M6P groups. The feature of LYTAC technology is its targeted degradation of proteins located outside or on the cell membrane. On June 29, 2020, a research paper entitled "Lysosome-targeting chimaeras for degradation of extracellular proteins" was published on the Nature from the research group of Professor Carolyn R. Bertozzi of Howard Hughes Medical Institute of Stanford University, and proposed the LYTACs.

AUTAC (autophagy-targeting chimera) is developed based on the autophagy pathway. In 2019, the Hirokazu Arimoto research team of Tohoku University in Japan took the lead in reporting this technology in the Molecular Cell.

ATTEC (autophagosome-tethering compound) was first published in Nature in 2019 by Professor Lu Boxun of the Academy of Sciences of Fudan University. In that study, Professor Lu Boxun verified the efficacy of ATTEC on the animal model of Huntington's disease (HD) at the cellular level.

Compared with PROTAC and other technologies that rely on the ubiquitination-proteasome pathway, the autophagy pathway-based pathways such as AUTAC and ATTEC can degrade insoluble protein multimers, and hope to be widely used in the treatment of neurodegenerative diseases in the future.

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