On February 28, BGB-16673, a BTK-targeted PROTAC drug of BeiGene, was launched for clinical trials for the first time in China. It is registered for clinical trials on ClinicalTrials.gov on August 16, 2021, with the indications including B-cell lymphoma, marginal zone lymphoma, follicular lymphoma and others. It is the initial PROTAC project launched by BeiGene.

PROTAC Technical Principles 

PROTAC (Proteolysis-targeting chimera) uses a ubiquitin-proteasome system to lead targeted protein into degradation. With one end of the PROTAC molecule connected to the target protein and the other to the E3 ubiquitin ligase, the two are linked together by force. This accelerates the transfer of the E3 ubiquitin ligase protein to the target protein. And the ubiquitinated target protein is able to be identified and degraded by the proteasome. The physiological functions held by the target proteins will disappear as the target proteins are degraded. In this way, a pioneering approach of biomedical research and pharmacy makes its way through degrading target proteins and regulating their physiological functions.

Advantages of PROTAC 

There are distinctive advantages of protein degradation agent of PROTAC, the greatest one of which is to target at the undruggable targets or mutant proteins, and conventional untargeted targets, including transcription factors and skeleton proteins. According to rough statistics, 80% of proteins in human cells are devoid of such sites. Surprisingly, PROTAC only needs to bind weakly to the target protein to specifically "mark" it. Therefore, the undruggable proteins are likely to be targeted by PROTAC technology, thus making a breakthrough on the conventional undruggable targets and overcoming the drug resistance. Besides, the drug, able to be reused since PROTAC shares an analogous reaction process with catalytic reaction, makes it possible to decrease the dose of the drug and enhance the safety. 

Overcome of Drug Resistance for BTK-PROTAC 

Small-molecule BTK inhibitors have been successfully applied in the treatment of B-cell lymphoma. However, the available BTK inhibitors in the market mainly produce enzyme inhibition through forming covalent bonds with cysteine residues of BTK active sites, which have great side effects and the drug-resistant mutations are easy to be produced by covalent binding, remaining a challenge in clinical treatment. However, the drug-resistant mutation of BTK-PROTAC can be resolved. In case that it can be marketed successfully, it can make more clinical benefits and better therapeutic drugs available for patients with B-cell malignant tumors. 

Pioneering Enterprises of PROTAC: Arvinas 

Arvinas is a new company of PROTAC technology globally, intending to selectively and efficiently degrade and get rid of morbific proteins by taking advantage of the human body's own natural protein processing system. Till now, Phase II clinical trials of two PROTAC drugs of the company have been launched, which are ARV-110 targeted androgen receptor (AR) and ARV-471 targeted estrogen receptor (ER). 

Applied in Metastatic Castration-Resistant Prostate Cancer (mCRPC), ARV-110 will directly smash androgen receptor, hopefully augmenting the efficacy of conventional "possession" mechanism. Furthermore, ARV-110 is able to degrade the replication of the target protein. Hence, it is likely to handle the overexpression and mutation of it, which remain crucial factors for drug resistance. 

The indication of ARV-471 is locally advanced or metastatic ER+/HER2-breast cancer. Regardless of the achievements of estrogen receptor inhibitors such as letrozole and fulvestrant in treating breast cancer, the drug resistance aggravates lots of patients' condition. Making use of PROTAC technology to degrade ER protein, ARV-471 is likely to handle the treatment of ER+ breast cancer. 

On July 22, 2021, Arvinas and Pfizer proclaimed that they would develop and commercialize ARV-471 together. Based on the agreement, Arvinas will get an advance payment of US$ 650 million and a milestone payment of US$ 1.4 billion. 

Besides, large pharmaceutical companies and bio pharmaceutical companies with PROTAC in the world include Pfizer, MSD, Genentech, AstraZeneca, Boehringer Ingelheim, GSK, Celgene, Amgen, Eli Lilly, Gilead, AbbVie, Johnson & Johnson and so on. 

R&D of PROTAC in China 

Although Arvinas holds the leadership in PROTAC, Chinese pharmaceutical companies endeavors to keep pace with it. 

Kintor Pharmaceuticals: GT20029 of Kintor Pharmaceuticals is the first PROTAC approved for clinical trials in China and the first AR-PROTAC for external use in the world. GT20029 is an AR degradation agent applied locally to the skin, which is able to efficiently cut the signaling pathway of androgen receptor and its physiological functions, so as to treat androgenetic alopecia and acne. GT20029 avoids the weaknesses of high molecular weight and poor oral bioavailability of PROTAC, and is applied for external and local skin administration, effectively reducing exposure and promoting local efficacy of drugs simultaneously. 

GT20029 was granted by the NMPA to carry out Phase I clinical research in April 2021, and was granted by the FDA for clinical research on July 13 of the same year. On July 28, 2021, the first batch of subject was administered in Phase I clinical trials of GT20029. 

HAISCO: HSK29116 is an innovative Class 1 pharmaceutical chemicals researched and developed by HAISCO. It is an oral PROTAC small-molecule antitumor drug, which can selectively inhibit BTK kinase activity and interfere B-cell development by regulating signaling pathway, thus curbing the course of various B cell malignant tumors.   

On the one hand, HSK29116 can directly inhibit BTK activity through specifically binding to BTK; on the other hand, it can trigger BTK ubiquitin to be marked and degraded through proteasome pathway, thus cutting off the transmission of BCR signaling pathway, refraining the development and proliferation of B-cell lymphoma cells, and playing a dual anti-tumor role. On April 6, 2021, HSK29116 was granted for clinical trials with the indication being B-cell lymphoma.

Hinova Pharma: Hinova Pharma boasts three kinds of PROTAC drug, which are AR-PROTAC HP518, AR-sv-PROTAC HC-X029 and SHP2-PROTAC HC-X035. 

HP518 is an AR-degrading oral PROTAC drug applied for the treatment of prostate cancer. The mechanism of action is that the target recognition section and E3 ubiquitin ligase recognition section of PROTAC molecule recognize and connect the target AR and E3 ubiquitin ligase simultaneously and respectively, and narrow the distance, which drives the ubiquitin protein to transfer and mark the target protein with polyubiquitin protein, and then accelerates the degradation of target protein by proteasome. 

Accutar Biotech: AC0682 is an oral PROTAC independently researched and developed by Accutar Biotech, intending to target and degrade ERα protein efficiently and selectively. ERα is a hormone-regulated transcription factor, holding a crucial role in the occurrence and proliferation of breast cancer. In nearly 80% of breast cancers, ERα is expressed. On September 2021, AC0682 was granted by the FDA to carry out Phase I clinical trials, with the indication being ER+/HER2-locally advanced/metastatic breast cancer. 

In the past 20 years, PROTAC has grown from creating innovative thoughts to successfully launching clinical development of many compounds, and from being suspected to the hot frontier of small-molecule drug R&D, this technology is likely to make a "first-in-class" breakthrough on undruggable targets and brand-new targets. Except for tumors, PROTAC is mostly applied in diseases of inflammation, virus, immune, neurology and neurodegeneration. It is estimated that many varieties of PROTAC will enter clinical trials in the next few years, which has attracted great attention from a large number of pharmaceutical companies, and many ventures invest into the technological development industry of PROTAC. With a wide range of targets and a massive market, PROTAC is hopeful to benefit more and more patients through technological advancement and promotion, as successful as small molecule inhibitors, monoclonal antibodies and immunotherapies. 

References:

1. PROTAC targeted protein degraders: the pastis prologue. Nat Rev Drug Discov. 2022 Jan 18 : 1–20.

2. Bekes, M.; Langley, D. R.; Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 2022, ahead of print.