Recently, Shanghai Yuyao Biotechnology Co., Ltd. (hereinafter referred to as "Yuyao Bio") cooperated with East China Normal University in ACS Central Science (if 18728) published a study titled Discovery of the Highly Selective and Potent Stat3 Inhibitor for Pancreatic Cancer Treatment**.
The study found a novel STAT3 selective small molecule inhibitor (YY201, code "YY002" in **) and demonstrated that it has significant anti-tumor effects on a variety of tumors, including pancreatic cancer. YY201 ASThe world's first highly active bifunctional phosphorylation inhibitor, preclinical studies have shownIt has excellent effect on complex and refractory tumors such as pancreatic cancer, triple negative breast cancer, and leukemia。At present, YY201 is being studied in China and the United States, which is expected to bring a new dawn to cancer patients around the world.
Stat3 target drug developmentIt is a common problem all over the world
Signal transduction and activator protein 3 (stat3), as an important physiological regulatory protein target in the human body, has been confirmed to have a regulatory effect on the cell growth cycle and immune response, and is highly expressed in most tumors, playing a very key role in tumors and autoimmune diseases, and has become the "star" drug target of the above diseases.
Due to the relatively flat interface of the STAT3 target, it cannot provide a "pocket" structure of drug design, and is recognized as a "difficult-to-drug target", and there is currently no related drug on the market in the world. At present, drugs in the clinical research stage have poor activity and are unit point inhibitors, which are easy to lead to drug resistance or poor efficacy, and patients urgently need the advent of new products.
The function of STAT3 is highly dependent on the phosphorylation of two switches on its protein, tyrosine STAT3tyr705 at position 705 and serine STAT3Ser727 at position 727, thereby activating the protein. Activated proteins induce tumors and other diseases by regulating gene expression, mitochondrial oxidative phosphorylation, and other functions.
At present, the main development strategy of global Stat3 small molecule inhibitors is to inhibit Pstat3tyr705 alone, but most of the inhibitory activity is at the micromolar level, and the poor activity greatly limits its clinical application. In addition, the existing small molecule inhibitors of STAT3 are not highly selective, and cannot efficiently and selectively inhibit STAT3 in STAT family proteins, which has a high risk of off-target, and the drug has a significant safety profile. Based on this, it is necessary for pharmaceutical companies to find a new generation of ** solutions and develop STAT3 bifunctional phosphorylation inhibitors with higher activity and higher selectivity, which will fully and specifically block intratumoral STAT3 activity and bring hope to clinical patients.
A team of scientists started a businessCompounds in the lab become medicines in the hands of patients
It usually takes 10 years and $1 billion for a drug to be successfully launched, and our core R&D team got together 10 years ago when we were still in school and started to develop new drugs for the STAT3 target. Zhou Wenbo, CEO of Yuyao Biotechnology, introduced.
Ten years ago, Zhou Wenbo and Chen Huang (co-first authors), who were doctoral students at East China Normal University, discovered that stat3 protein plays an important role in the pathogenesis of tumors, autoimmune diseases and other diseases.
Although the project had been established in the research group at that time, it was difficult to combine the designed compounds due to the extreme difficulty in the development of STAT3 drugs and the smooth target pockets. The preparation steps of compounds are complex, and it takes dozens of steps to synthesize a batch of compounds, which takes several weeks. Compounds need to be verified at multiple levels such as molecular, cellular, and animal, and the consistency of multiple drug screening systems is not good, many times a batch of compounds are verified in the molecular or cellular system, but the effect will be greatly reduced when experiments are carried out in animals, or drug toxicity problems occur, and the screening system needs to be built from scratch and the parent nucleus of the compound needs to be redesigned, and the whole process is difficult. Finally, after 3 years of repeated screening and compound optimization, a number of single-target inhibitors with potential effects were finally developed
Although the activity of these single-target inhibitors has been comprehensively superior to the current STAT3 monophosphorylation inhibitors, combined with the activation characteristics of STAT3, the team proposed to further improve the effect of the compounds and consider the possibility of developing a new class of compounds, STA3 dual-site phosphorylation inhibitors. "This new idea was extremely challenging, and very few teams in the world were working on it at that time," Zhou recalls the scene.
The team restarted the development of STAT3 dual phosphorylation inhibitors, and this time, based on the previous experience in the development of monophosphorylation inhibitors, it took only 2 years to develop a class of highly active and highly selective STAT3 bifunctional inhibitors - YY201! This kind of inhibitor can inhibit the bifunctional phosphorylation of STAT3 in vitro and in vivo, with excellent inhibitory activity and selectivity, and compared with multiple STAT3 small molecule inhibitors in clinical studies, YY201 activity is more than 1000 times better than the above inhibitorsAt present, it is the world's first nanomolar activity level STAT3 dual phosphorylation site inhibitor, a real "world-first" new drug。At the same time, YY201 also has excellent druggability, such as oral administration, high bioavailability, and low toxicity in the body, and is expected to become a potential drug for pancreatic cancer, breast cancer, leukemia and other diseases in the future.
At that time, the vast majority of colleges and universities were mainly engaged in basic research, and the final destination of the research results of most laboratories was a few first-class articles and patents, so they buried themselves in other topics, and it was difficult to transform and implement good laboratory results.
In addition to YY201, a number of projects of Liu's team have screened a series of small molecule compounds that are safer and more effective than existing drugs, and some targets even have no marketed drugs, which may be the only hope for cancer patients to survive. Liu Mingyao gradually realized that the results of academic research could not be left only in the laboratory, and began to think about how to transform the results in his hands into life-saving medicines. Subsequently, Zhou Wenbo and his team members, who had the same idea, founded Yuyao Biotech to make innovative drugs developed from their own laboratories.
Relying on the "Big Zero Bay" innovation ecological zoneTake the last mile of innovation
As a start-up enterprise of teachers and students of East China Normal University, relying on the innovative achievements of East China Normal University, in order to strengthen scientific research exchanges with universities, the company set its sights on "Da Zero Bay" when selecting the site. Looking back now, Zhou Wenbo still lamented that "it is a very forward-looking and strategic choice".
In 2023, the Shanghai Science and Technology Commission, together with a number of units, will release the "Plan for Promoting the Construction of the "Da Zero Bay" Science and Technology Innovation Source Functional Zone", which concretizes the future development strategy of the "Da Zero Bay", and has more than 1,000 start-up enterprises in the park, Shanghai Jiaotong University and East China Normal University, relying on the high-density innovation resources and high-level innovation capabilities of regional universities and institutes, through enterprises to play the main role, guided by market demand, and integrating innovation chain, industrial chain and talent chain. Realize the precise docking of production, education and research, and the open science and technology innovation block has begun to take shape.
Through cooperation with East China Normal University, Tongji University, Fudan University and other universities, as well as Ruijin Hospital, the First Affiliated Hospital of Zhejiang University, Sun Yat-sen University Cancer Prevention and Treatment Center and other hospitals, Yuyao Biotech has carried out an integrated cooperation model of "industry-university-research-medicine" in the form of technology development and research cooperation, carried out technical exchanges and technical research, fully mobilized the advantages of all parties, linked multiple resources, and promoted the research and development of product pipelines.
With the help of the good innovation and entrepreneurship ecological environment of "Da Zero Bay" and the support of various policies in Shanghai, Yuyao Biotech has grown into a biotechnology enterprise in the clinical research stage in less than four years since its establishment, and has successively won the titles of high-tech enterprise, "specialized, special and new" small giant enterprise in Minhang District, and cutting-edge science and technology entrepreneurship enterprise in Minhang District, and has undertaken a number of city-level scientific research projects.
Yuyao Biotech adheres to the development concept driven by scientific and technological innovation, in addition to insisting on GPCR targets, it also pioneers the "super molecular glue" technology in the track of "difficult-to-drug targets". In 2022, it was highly recognized by the expert judges in the second "National Disruptive Technology Innovation Competition" of the Ministry of Science and Technology of the People's Republic of China and won the national award.
The new paradigm of industry-university-research-medical cooperation is gradually becoming the business card of industry-university-research development of "Da Zero Bay", and also provides new solutions for other similar companies.
Editor: Cui Songge.
*: Shanghai Yuyao Biotechnology *** Shanghai Science and Technology.
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