Focus on PROTAC—Target Summary from 2001 to 2019

PROTAC, of which the full name is proteolysis-targeting chimera, looks like a dumbbell and mainly consists of a linker, a ligand of interest protein, and a ligand recruiting E3 ubiquitin ligase. In other words, one end of the PROTAC molecule binds to the target protein and the other end to E3 ubiquitin ligase. E3 ubiquitin ligase can mark a small protein called ubiquitin as defective or damaged by attaching it to the target protein. After that, the labeled target protein will be degraded by the cell proteasome system to remove the target protein.

Some researchers believe that protein degradants based on PROTACs technology may be the next blockbuster drug. In the past two years, there are frequent research results related to PROTACs in academic field. In the industrial field, drug research and development based on this technology has become a hot spot from start-ups to pharmaceutical giants, which cannot hide their enthusiasm for PROTACs. It’s worth mentioning that with the disclosure of positive phase I clinical data of ARV-110, the world’s first small molecular protein degrader based on PROTACs, researchers’ confidence in the clinical transformation of this technology has greatly increased.

From the publication of the first proof-of-concept study in 2001 to the first clinical trial of PROTACs in 2019, this technique has developed into a chemical biological method and a new treatment. In early stage, the E3 ligase binding motif of PROTACs was peptide, which led to limited cell permeability and poor degradation of PROTACs. With the development of more drug-like ligands of VHL E3 ligase and the elucidation of the mode of action of thalidomide, PROTACs technology has made breakthroughs. These findings also pave the way for the development of the first drug-like PROTACs targeting RIPK2/err α 12 and BRD4 reported in 2015. As these pioneering studies accelerated the development of this field, academic and industrial interests in PROTACs-induced protein degradation greatly increased. Since then, many research groups focused on exploring the strengths, opportunities, limitations and weaknesses of the technology.

At present, there are two clinical trials under rapid progress, one is the small molecule protein degrader ARV-110 targeting androgen receptor (AR) in patients with metastatic castration-resistant prostate cancer (mCRPC), and the other is the small molecule protein degrader ARV-471 targeting estrogen receptor (ER) in metastatic ER+ positive/HER2 negative breast cancer patients.

In terms of target selection, in addition to the previously mentioned targets such as AR, ER and BRD4, a large number of proteins became the choice of researchers since 2001.

Compared with traditional protein inhibitors, PROTACs-based protein degradants show unique advantages. For example, targeted degradation induced by PROTACs can turn off the scaffold function of FAK, which cannot be achieved by small molecular FAK inhibitors. PROTACs targeting SMARCA2/4 shows the same advantage. SMARCA2/4 is part of the BAF complex and is notoriously difficult to target. In addition, it was reported that Tau degradants can remove the accumulated proteins in the neuronal cell model of patients with frontotemporal dementia (FTD), extending the potential therapeutic application of PROTACs to neurodegenerative diseases. These studies prove that PROTACs have great potential to expand the variety of targeted proteins. Below is a table of the most reported PROTACs targets and the corresponding E3 ligases.

Table 1. Proteins that are successfully degraded by PROTACs

So far, the research of protein degradants mainly focuses on tumor, and has made some progress in the fields of neurodegenerative diseases, inflammation & immunology. Although there are still challenges and obstacles, the initial success so far bodes well for the bright future of PROTACs.

It is highly anticipated that PROTACs-induced protein degradation will outstandingly address the disease that are difficult to deal with.