Targeted protein degradation (TPD) is an emerging therapeutic approach that has received much attention because of its therapeutic potential to modulate proteins that are difficult to target with traditional small molecules. Proteolysis targeting chimera (PROTAC) utilizes the natural protein degradation system in cells, the ubiquitin protease system (UPS), to achieve the targeted degradation of the target protein (POI). PROTAC is a heterobifunctional small molecule, one end targets POI, and the other end recruits E3 ubiquitin ligase to form a dumbbell-shaped ternary complex. POI is labeled with ubiquitin, which is then recognized and degraded by proteasome.

In 2019, the first PROTAC molecules entered clinical trials. In 2020, clinical proof of concept for PROTACs targeting estrogen receptor (ER) and androgen receptor (AR) cancer targets was demonstrated. With this success, the TPD field is now ready and committed to targets that are considered "untreatable".

What’s PROTAC?

The concept of PROTAC was first proposed by Crews et al. in 2001. It can use the naturally occurring protein clearance system in the body to reduce protein levels rather than inhibit the function of proteins, and play the purpose of treating diseases. Ubiquitin-dependent proteolysis is the main pathway for degrading intracellular proteins and is part of normal cellular maintenance physiology. In this pathway, proteins are degraded by the proteasome in a three-step process, including ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), which coordinate ubiquitin molecules to target proteins (substrate) transfer.

PROTAC is a heterobifunctional molecule that can be divided into three parts: the first part connects the ligand that binds the target protein, the second part connects the ligand that binds the E3 ligase, and there is a ligand in the middle that links the first and second parts together. Its mechanism of action is very simple, is first the target protein and E3 ligase together. After the formation of the triplet complex, the ubiquitin enzyme is automatically transferred to the target protein, and the proteasome targets the degradation of the target protein by recognizing the ubiquitin enzyme on the target protein.

Advantages of PROTAC

First, PROTAC molecule has catalytic degradation function. Whereas each small inhibitor can only act on one protein molecule, each PROTAC molecule can degrade many protein molecules, so a very low dose can have a good effect. And as long as there is a small amount of PROTAC in the cell, the effect can be maintained.

Second, the traditional mode of action of small molecules and antibodies requires high concentrations of inhibitors or mAbs to occupy the active site of the target and block the transduction of downstream signaling pathways. The PROTAC does not affect the function of the protein, but mediates the degradation of the target protein. It is not necessary to act on the active site of the protein to inhibit its activity, but only to have a certain binding rate with the target protein. Therefore, more target proteins can be selected to bind, and it may act on some targets that are not available for drug production in the traditional sense.

Third, because PROTAC works by degrading the target protein, PROTAC can overcome the problem of small-molecule drug resistance when the resistance is caused by the cell synthesizing more target protein. In summary, PROTAC technology combines the advantages of small molecule chemical drugs, large molecule biological drugs and RNAi molecules, and has the potential to be a key technology to generate the next wave of blockbuster drugs.

Development of PROTAC

The first era of PROTAC began with the publication in 2001 of the pivotal PROTAC paper by Sakamoto et al., which was the first proof of concept in vitro for PROTAC. Protac-1 is designed to target methionyl aminopeptidase 2 (METAP2), a potent target for angiogenesis inhibition. Protac-1 consists of two domains: ovalicin and a 10-amino acid phosphopeptide derived from nuclear factor-κB inhibitorα (NF-κBiα), which is recognized by the E3 ligase β-transductor repeat (β-TRCP). Protac-1 acts as a link between METAP2 and β-TRCP, enabling the ligase to ubiquitinate METAP2.

Subsequently, a peptide derived from hypoxia-inducible factor 1 subunit-α (HIF1α) that binds vonHippel–Lindau (VHL) E3 ligase was discovered to engineer cell-penetrating PROTACs that degrade a range of POIs. Technically, these early PROTACs are now considered "biological PROTACs" because they are not complete small-molecule structures, but instead contain peptide ligands for E3 ligases. However, the discovery of small-molecule mimetics of HIF1α peptides opened the door for the design of PROTACs based solely on small-molecule structures. Since then, molecular development in this area of PROTAC has grown exponentially.

This foundational era of TPD was ended with the first PROTAC drug to enter clinical trials in 2019, ARV-110, which targets the androgen receptor by recruiting it to the CRL4–CRBN ligase complex. Since then, PROTAC has entered an era of clinical translation, where multiple molecules designed to degrade disease-causing proteins enter the clinic and the field becomes extremely hot.

The commonly used linkers in the development of PROTACs are PEG products. Biopharma PEG is a professional PEG derivatives supplier that provides multi functionalized PEG derivatives as PROTAC linkers. “We have our own factory and over 3000 high purity PEG linkers in stock.” said our Production Director, “We are able to empower our customers’ PEGylation, bioconjugation, ADC drug development for pharmaceutical and biotech R&D.”

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