PROTACs, full name is Proteolysis-Targeting Chimeras. Its structure looks like a dumbbell. It connects the "ligand of the interest protein" and "recruiting ligand of E3 ubiquitin ligase" through a "linker". In other words, one end of the PROTACs molecule is bound to the interest protein (target protein), and the other end is bound to the E3 ubiquitin ligase. The E3 ubiquitin ligase can mark the target protein as defective or damaged protein by attaching a small protein called ubiquitin to the target protein. After that, the cell's protein shredder (proteasome) degrades the labeled target protein.
PROTACs mode of action (source: Royal Society of Chemistry)
In March 2019, an article issued on Nature stating that protein degradation agents based on PROTACs technology may become the next blockbuster drugs. In the past two years, research results related to PROTACs have appeared frequently in the academic field. In the industrial field, drug development based on this technology has become a new hot spot. From start-up companies to pharmaceutical giants, it is difficult to conceal their enthusiasm for PROTACs. What's more worth mentioning is that with the release of positive phase I clinical data of the world’s first small molecule protein degradation agent ARV-110 based on PROTACs, the industry’s confidence in the clinical transformation of this technology has greatly increased.
In October 2020, a monograph entitled "Protein Degradation with New Chemical Modalities: Successful Strategies in Drug Discovery and Chemical Biology" edited by Professor Craig Crews of Yale University, a pioneer in PROTACs and Hilmar Weinmann, a scientist at Janssen Pharmaceuticals, was officially published. The book has 15 chapters and 359 pages. It provides a comprehensive overview of the recent research progress of leading scientists in this field and some of the current challenges in this field.
Source: Royal Society of Chemistry
The recommendation reads: Using small molecules to target protein degradation is one of the most exciting small molecule therapeutic strategies in decades, and it is also a rapidly developing research field. In particular, the development of PROTACs has opened up new ways to solve traditionally difficult-to-target proteins. For researchers in the fields of drug development and chemical biology, this book will be an ideal conference book.
In the first chapter which can be read free, Professor Craig Crews, Hilmar Weinmann, and Bayer scientist Philipp M. Cromm reviewed the development of PROTACs, discussed the optimization of PROTACs, and whether the targeted degradation mediated by this technology can change the paradigm of drug research and development.
The article pointed out, since the first proof-of-concept study was published in 2001, and PROTACs entered clinical trials for the first time in 2019, the technology has developed into a chemical biology method and a new therapeutic approach.
In the early stages of technology development, the E3 ligase binding motif of PROTACs was peptides, which resulted in limited cell permeability of PROTACs and poor degradation effects. Breakthroughs were made in the PROTACs technology with the development of VHL E3 ligase peptide ligands with more drug-like properties and elucidations of the mode of action for thalidomide (such drugs can redirect the E3 ubiquitin ligase CRBN, thereby making the transcription factors IKZF1 and IKZF3 polyubiquitinate, leading to the degradation of IKZF1 and IKZF3 by the proteasome). These findings also paved the way for the development of the first drug-like PROTACs targeting RIPK2/ERRα12 and BRD4 reported in 2015. As these groundbreaking studies have greatly accelerated the development of this field, the academic and industrial field have greatly increased their interest in protein degradation induced by PROTACs. Since then, many research groups have focused on exploring the advantages, opportunities, limitations, and weaknesses of this technology.
PROTACs development timeline (source: Royal Society of Chemistry)
In order to promote protein degradation agents based on PROTACs technology to the clinic, Professor Crews established Arvinas in 2013. Afterwards, C4 Therapeutics (2015) and Kymera Therapeutics (2017) were established one after another to explore the therapeutic potential of small molecule protein degradants. At present, these three companies have reached cooperation with many large pharmaceutical companies. In fact, whether it is cooperating with start-up companies or setting up a protein degradation department by itself, almost every pharmaceutical company has begun to evaluate PROTACs technology, such as Novartis, AstraZeneca, and GSK.
At present, Arvinas has the fastest project progress. The company was the first to start two clinical trials in 2019. One is investigating ARV-110, a small-molecule protein degrading agent targeting the androgen receptor (AR) in patients with metastatic castration-resistant prostate cancer (mCRPC). The other one is investigating ARV-471, a small-molecule protein degrading agent targeting the estrogen receptor (ER) in patients with metastatic ER+ positive/HER2 negative breast cancer.
In terms of target selection, in addition to the aforementioned AR, ER, BRD4 and other targets, a large number of proteins have become the choice of researchers in the field of PROTACs since 2001. The following table summarizes most of the reported PROTACs targets and the corresponding E3 ligases in chronological order.
Proteins that were partially successfully degraded by the PROTACs ubiquitination pathway (source: Royal Society of Chemistry)
Compared with traditional protein inhibitors, PROTACs-based protein degradation agents have unique advantages. For example, for focal adhesion kinase (FAK), the targeted degradation induced by PROTACs can turn off the stent function of FAK, which cannot be achieved by small molecule FAK inhibitors. PROTACs targeting SMARCA2/4 also showed the same advantages. SMARCA2/4 is part of the BAF complex and is notoriously difficult to target. In addition, studies have also reported that Tau degrading agents can eliminate accumulated proteins in neuronal cell models derived from patients with frontotemporal dementia (FTD), expanding the potential therapeutic field of PROTACs to neurodegenerative diseases. These studies have proved that PROTACs have great potential to expand the types of targetable proteins.
So far, the research of protein degradation agents has been mainly concentrated in the field of tumors, and has been found in the fields of neurodegenerative diseases inflammation and immunology. Although there are still many challenges and obstacles to overcome, the initial success achieved so far indicates a bright future for PROTACs. The three authors said that in the future, the protein degradation induced by PROTACs will solve the outstanding and intractable disease drivers, which is very exciting.
The commonly used linkers in the development of PROTACs are PEGs, Alkyl-Chain and Alkyl/ether. Biochempeg, a leading PEG supplier provides multi functionalized PEG derivatives as PROTAC linkers to customers all over the world .
1#Protein Degradation with New Chemical Modalities: Successful Strategies in Drug Discovery and Chemical Biology (Royal Society of Chemistry)
 Peptide PROTAC in Drug Development
 PROTACs and Targeted Protein Degradation