Over the past decade, major changes have taken place in the field of drug targets. Although traditional targets (such as kinases and G-protein-coupled receptors) are still the main stream, the focus is gradually shifting to more challenging “undruggable” targets that usually refer to proteins without enzyme function, which account for about 80% of human proteins. At present, the hotspot PROTAC technology reveals great potential in overcoming drug resistance and targeting non-druggable targets.
At present, although the research and development of macromolecular biological drugs (monoclonal antibody, double antibody, ADC, and interferon) is hot, small molecular drugs are still the main battlefield of new drug research and development because of their unique advantages (relatively low R&D cost and relatively skilled technology).
In the process of continuous exploration of pharmaceutical chemistry, researchers are developing new strategies to target disease driver proteins. Protein degradation induced by small molecules has attracted the most attention in recent years. By controlling the fate of proteins and inducing their degradation, drugs target not only enzymes, but also inactive sites or non-proprietary protein targets, such as scaffolding proteins targets. To this end, scientists have discovered the mechanism that uses the cell’s own protein degradation mechanism to label the selected target protein and trigger its degradation. The ubiquitin proteasome system is the core, which controls the fate of proteins through ubiquitin and subsequent proteasome degradation. PROTACs technology makes use of this degradation mechanism, so that the target protein is irreversibly removed in a proteasome-dependent way, which is a completely different mode of action from traditional small molecule inhibitors and even antibodies.
Pros and Cons
The advantage of PROTAC is that it can not only effectively inhibit the target protein, but also degrade and remove quickly. It’s worth mentioning that only the catalytic dose of drugs can degrade intracellular target proteins, so it has high safety, drug resistance, and broad application prospects. Although PROTACs have shown remarkable effectiveness, there are still limitations that need to be addressed.
The molecular weight of PROTACs is generally between 700 and 1200, resulting in poor membrane permeability and (oral) bioavailability poor, and lacking in a prediction model such as the “five principles of drugs” suitable for small molecular drugs, which makes most of the current studies only prove the effectiveness of the designed PROTAC on target protein degradation and anti-proliferation activity at the cellular level.
- Different from traditional small molecular drugs, there is no effective high-throughput screening technique to quickly and massively evaluate the ability of PROTAC to degrade POI, which can only be achieved by cell activity screening or Western blotting, greatly reducing the speed and success rate of PROTAC development.
- It was reported that simply changing the length or structure of the linker will affect the degradation ability of PROTAC greatly, which may be caused by the different spatial distances between different E3 enzymes and POI in the process of ubiquitin. In view of the fact that the crystal structure of the POI-Protac-E3 enzyme complex has not been resolved at present, there is a lack of guidance for the transformation of the linker.
- It is found that the substrate that specifically binds to E3 enzyme receptor protein is accidental. At present, the mainly reported PROTAC targets are CRBN and VHL. Although it is unknown whether CRBN and VHL will mutate and whether the mutation will affect PROTAC, it is of great significance to study new E3 enzyme and develop corresponding PROTACs, and it is challenging.
Although some common proteins (such as BRD4, androgen receptor, or BTK) have been selected as targets in many studies, almost every day there are reports that new target proteins can be degraded by PROTAC. For most protein targets, the effect of PROTAC-mediated degradation is similar to that of traditional targets, and PROTAC molecules are superior to some inhibitors in the effect or solving some drug resistance mechanisms. For example, the degradation of target focal adhesion kinase induced by PROTAC can turn off the signal transduction function of FAK, which can not be achieved by small molecular FAK inhibitors. In addition, PROTAC was reported to remove Tau protein from neurons derived from patients with frontotemporal dementia, and these models extend the treatment area of PROTAC to neurodegenerative diseases. Such kind of research proves the great potentials of PROTAC in the field of drug therapy.