Release date:2022/4/15 18:23:45

In the context of the increasing popularity of macromolecular drugs such as monoclonal antibody drugs, dual antibody drugs and ADCs, small molecule drugs have once again become the focus through PROTAC (Proteolysis targeting chimera), a breakthrough new technology. 

After 20 years of development, PROTAC technology has attracted the attention of many pharmaceutical companies, such as Pfizer, Bayer, Novartis and other multinational pharmaceutical companies.

Professor Craig M. Crews of Yale University, co-founder of Arvinas, recently published a review in Nature Reviews Drug Discovery that summarized the development of PROTAC over the past 20 years. Four major development directions for PROTAC in the next 20 years are discussed.  

Introduce PROTAC

Many targets that play key roles in cancer and other diseases are notoriously difficult to become drug, some of which are difficult to bridge with small molecules due to their wide and shallow active sites. Others have "smooth" surfaces with few sites for small molecules to bind to.  

But with the continuous development of PROTAC technology, these undruggable targets have also become within reach.

PROTAC techonoly uses heterozygotic bifunctional small molecule compounds to bring the target protein and the intracellular E3 ubiquitin ligase closer, and specifically degrades the target protein in vivo through the ubiquitin-proteasome protein degradation pathway. The drug is composed of 3 parts, that is, one end is the specific E3 ubiquitin ligase ligand, the other end is the specific ligand of the target protein and the linker in the middle, thus forming the "target protein-PROTAC-E3 ubiquitin ligase".

Unlike traditional small-molecule drugs, PROTAC drugs do not need to bind tightly to the disease-causing target for long periods of time to degrade it.  By destroying protein targets rather than inhibiting them, problems of non-drugability and drug resistance are solved.

 PROTAC-targeted protein

Table 1. PROTAC-targeted protein degraders in clinical development

Four major trends in the future development of PROTAC

In the past few years, PROTAC technology has basically matured. The authors propose that the next milestones in the field of PROTAC will focus on the following four areas, namely, identifying optimal protein degradation targets, expanding the scope of clinical application of E3 ligase, expanding the scope of clinical treatment beyond oncology and developing other PROTAC modes.  

1. Identify optimal protein degradation targets

The first wave of clinical phase proteolytic agents selected are clinically proven mature targets. Targeted products have been developed with moderate success, and the potential of PROTACs as a therapeutic modality has been validated. The real promise of the technology, however, is in enabling those undruggable targets.

In this paper, "Principles of PROTAC targets" (see figure below) are proposed, including: changes that deviate from the natural state through overexpression, mutation, aggregation, isomer expression or fine localization, leading to disease by means of functional acquisition; a binding surface accessible to E3 ligases; ideally, a structure-free region capable of accessing the proteasome.

Proteins with drug resistance mutations to targeted therapy, proteins with backbone functions, and proteins that are "undruggable" by other therapeutic modalities may also be suitable PROTAC targets. 

PROTAC target

Principles of PROTAC Targets (Source: References)

2. Expand the scope of clinical application of E3 ligase

More than 600 E3 ubiquitin ligases are encoded in the human genome. However, only a few E3 ligases (VHL, CRBN, etc.) are currently used for PROTAC design. How to expand E3 ubiquitin ligases that can be used for PROTAC technology is also one of the challenges PROTAC faces. 

The authors propose that new E3 ligases can be found in the following ways.

A practical and valuable approach is to find broadly applicable, ubiquitous ligases, similar to CRBN and VHL. They can be paired with any target protein, allowing unrestricted application in multiple therapeutic indications.

Another approach, based on key characteristics of ligases, such as tissue and cell specificity, tumor enrichment, and tumor necessity, could provide development opportunities for domain-specific protein degradation therapies. Interestingly, some ligases exhibit "reverse specificity" (low expression in specific tissues or cell types), which may also present opportunities for protein degraders.

In addition, another new frontier in precisely targeting protein degradation is PROTAC molecules that specifically target tumor cells, which can be achieved by targeting tumor-specific or tumor-enriched E3 ligases.

3. Expanding the scope of clinical treatment beyond oncology

So far, research on protein degraders has mainly focused on the oncology field, but since protein degraders may degrade any chosen target, their application can be broader. In fact, in recent years, protein degraders have gradually been used in fields other than oncology, such as neurodegenerative diseases. And there is a breakthrough in inflammation/immunology field.

Following the success of immune checkpoint inhibitors, the development of small molecule drugs that can stimulate the anticancer immune response is an important area of drug development.  PROTAC molecules can activate immune cells in the mode of small molecule drugs and mimic the effects of PD-1/PD-L1 targeted therapy, thus becoming a potential "first-in-class" therapy.  Recently, PROTAC molecules targeting MAP4K1 have shown promising preclinical activity. 

One of the key features of PROTAC molecules is their ability to degrade proteins that are not targeted by traditional small-molecule inhibitors because they lack an active site. This feature makes proteins that accumulate in various neurodegenerative diseases (such as Tau) become potential targets.

4. Develop other PROTAC modes

In addition to PROTAC, various novel protein degradation technologies have been developed, further expanding the range of targets that can be targeted by this technology.

The authors define three types of PROTACs: traditional small-molecule PROTACs, PROTACs of peptides or other biological products ( bioPROTACs ), and PROTACs containing both peptide and traditional small-molecule "warheads" (hybrid PROTACs).

BioPROTACs are based on genetic coding to directly fuse peptides, fusion proteins, and oligonucleotides with E3 ligases, which bind and degrade target proteins through peptide or protein recognition domains. Since BioPROTAC relies on genetic coding, there are certain limitations.

The article pointed out that the past 20 years is prologue, and the field of targeted protein degradation has been ""poised to challenge", challenging targets that were previously considered "undruggable". Although there is no drug approved by the FDA so far, PROTAC will eventually usher in its era after more than 20 years of technical accumulation.

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Related articles:
[1] PROTACs VS. Tranditional Small Molecule Inhibitors
[2] PROTAC And Other Protein Degradation Technology 
[3] Summary of PROTAC Degraders in Clinical Trials

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