New breakthrough in protein degradation: Tsinghua Chen's team has developed proTAC peptides targeting beta-catenin for the first time, effectively suppressing colon cancer.

Abstract: Recently, Professor Chen yeguang of Tsinghua University and Professor Hu Honggang of Shanghai University reported for the first time that xtax VHL, a protac peptide targeted to degrade β - Catenin, can directly recognize β - Catenin protein and promote its degradation through ubiquitination proteasome pathway. It can not only inhibit Wnt signal at the cell level, but also play a good role in a variety of mouse tumor models Tumor suppressor effect, more importantly, can also play an important role in tumor like organs of patients with colon cancer.protac (proteolysis targeting chimera) technology links E3 ubiquitin ligase with target protein, resulting in ubiquitination of target protein, which is decomposed into peptides and amino acids by proteasome.after the target protein is degraded, protac will be released for reuse and continue to destroy the target protein.compared with other drugs and therapies, protac has many potential advantages, such as its wide tissue distribution and oral administration.compared with other therapies (such as cell therapy, antibody drugs, etc.), the production process of protac is simpler.compared with small molecule drugs, protac can target more targets which can not be targeted by small molecule drugs and produce better effect.in recent years, protac technology has developed rapidly and has been proved to be one of the most potential and breakthrough drug research and development technologies.especially at the recent ASCO meeting, protac technology has been brilliant.arvinas company of the United States has released the first phase clinical data of protac drug - arv-110 targeting androgen receptor is safe and effective in patients with metastatic castration resistant prostate cancer (mcrpc).protac start-ups such as arvinas, kymera, nurix, C4 therapeutics, cedilla, Monte Rosa, etc. have successively obtained huge amounts of financing, and international pharmaceutical giants such as BMS, Novartis, GSK, Merck, Pfizer, Bayer and other international pharmaceutical giants have set up in succession. We can almost foresee that in the near future, protac technology is likely to set off a wave of blockbuster drug listing.Colorectal cancer (CRC) is a cancer with high incidence rate and high incidence rate worldwide. With the increasing pressure of modern society, more people's diet habits tend to focus on fried foods such as oil and salt, and drinking. In the foreseeable future, the incidence of colon cancer may increase further.under the appearance of environmental factors and lifestyle, scientists have a deeper understanding of the molecular mechanism of colon cancer. Many genes have been found to have mutations in intestinal tumor tissues of patients, such as APC, TP53, KRAS, BRAF, PIK3CA, Smad4 and CTNNB1, involving Ras-MAPK, p53, PI3K, TGF - β and Wnt / β - catenin signaling pathways.The over activation of Wnt / β - Catenin signal pathway is the most important for the occurrence and development of colon cancer. More than 80% of patients with colon cancer have inactivated APC mutation or CTNNB1 activation mutation, which leads to the continuous accumulation of messenger molecule β - Catenin protein in cells, and eventually leads to the overactivation of Wnt / β - Catenin signal and the proliferation of cancer cells.therefore, inhibition of Wnt / β - Catenin signal to achieve the anti-cancer effect has become an attractive field.Wnt / β - catenin signaling pathway mainly includes Wnt ligand secreted outside the cell, receptor complex across cell membrane and degradation complex in cell, and the messenger molecule β - Catenin.on the one hand, in the past, most of the inhibitors targeting Wnt / β - catenin signaling pathway focused on the upstream of β - Catenin, which not only had side effects, but also could not overcome the activation and mutation of β - Catenin. On the other hand, almost all the inhibitors directly acting on β - Catenin were chemical small molecules, because β - Catenin had no enzyme activity and binding pocket with small molecules, and it could interact with other proteins It is difficult to completely inhibit the function of β - Catenin by this kind of small molecule inhibitors. Compared with small molecules, peptides have the advantages of large binding area and high specificity. In the past, it has been reported that the subscription peptide xstax can inhibit Wnt signal by binding to β - Catenin at the cellular level, but xstax is difficult to play in vivo effect.it has become a promising research direction to improve the biological activity of peptide inhibitors targeting Wnt / β - Catenin signal, so as to exert the anti-cancer ability in vivo. recently, Professor Chen yeguang of Tsinghua University and Professor Hu Honggang of Shanghai University, as co authors, published a research paper entitled "a protac peptide induces dual β - Catenin degradation and suppresses Wnt dependent internal cancer" in cell discovery magazine. in this paper, a novel chimeric peptide inhibitor xstax VHL was designed and synthesized based on the peptide xstax by using protein degradation targeting chimeric (protac) technology. This chimeric peptide can directly recognize β - Catenin protein and promote its degradation through ubiquitination proteasome pathway. It can not only inhibit Wnt signal at cell level, but also can inhibit Wnt signal in a variety of mouse tumors The model can also play a good role in tumor inhibition, and more importantly, it can also play an important role in tumor like organs of patients with colon cancer. because protac molecules are bifunctional molecules, one end recognizes and binds to the target protein, and the other end recruits ubiquitin ligase to promote the degradation of target protein. The researchers first used the subscription peptide sahpa1 (Wnt signal activating peptide) and xstax (Wnt signal inhibitory peptide) as the specific recognition part of β - Catenin, and then selected the recognition peptide alapyip as the ligand for recruitment of VHL ubiquitin ligase, Two protac chimeric peptides sahpa 1-vhl and xstax VHL were synthesized by chemical synthesis. experiments on various colon cancer cell lines showed that only xstax VHL showed significant degradation ability to β - Catenin. this indicates that chimeric peptide xstax VHL significantly improves the β - Catenin degradation ability and Wnt signal inhibition ability of lead peptide xstax, while sahpa1-vhl does not reverse the activation of Wnt signal by sahpa1. in nude mice subcutaneous tumor formation experiment, xstax VHL showed obvious inhibitory effect on the tumorigenicity of colon cancer cells. in addition, in the other two mouse models (apcmin / + mice and axin2lacz mice), xstax VHL was injected into mice, which significantly reduced the number of tumors, and proved that the anti-cancer ability of xstax VHL was exerted through the degradation of β - Catenin and the suppression of Wnt signal. finally, in addition to the mouse model, the researchers used tumor tissue from patients with colon cancer to culture tumor like organs, and then treated with polypeptides. It was found that the survival of most tumor like organs was significantly inhibited by the peptide xstax VHL, which proved the potential clinical application value of protac peptide xstax VHL. in general, this study is the first time to report the protac peptide xstax VHL, which can not only degrade β - Catenin and inhibit Wnt signal at the cell level, but also play a good role in tumor inhibition in vivo. this protac peptide can avoid the problem of insufficient inhibition of β - Catenin protein by small molecule inhibitors. of course, the current protac peptide xstax VHL still has the problem of high concentration. in the future research work, the researchers will optimize xstax VHL from various aspects, hoping to further improve its biological activity. paper links: