China has built the world's largest kinase target cell screening library

Release date: 2017-04-20

Recently, the Strong Magnetic Field Science Center of the Hefei Institute of Material Science, Chinese Academy of Sciences has established the world's largest high-throughput cell screening library based on cancer kinase targets. The cell bank contains nearly 70 cancer kinase targets, with more than 150 cell types, covering almost all of the kinase and kinase mutant cells currently known to be involved in tumorigenesis. The completion of the cell bank has filled the gap in such a detection system in the field of new drug creation in China, and will provide strong support for the development of new anti-tumor drugs.

The "precise medical treatment" of tumors mainly includes two aspects: precise diagnosis and precise treatment. It refers to the genetic background and pathological characteristics of tumor patients, determines the key factors of tumor incidence, and individually designs medication treatment programs. Specifically, many tumors are caused by mutations in certain growth-associated "kinases" leading to abnormal activation, and thus inhibitors against these mutant kinases are effective in inhibiting the activity of these kinases, thereby inhibiting the growth of cancer cells. purpose. The advantage of these "targeted drugs" is that they can inhibit carcinogenic targets with high specificity and interfere with the growth of cancer cells without affecting surrounding normal cells. Therefore, compared with conventional treatments such as chemotherapy, targeted drug therapy is not only accurate, but also reduces unnecessary damage to the patient's body, relieves pain, and strives for more treatment time to prolong life.

After more than ten years of development, the development of targeted high-response targeted drugs based on individualization has made great progress. More than 30 have been used clinically, but these drugs can only cover more than 10 kinds of cancers. Certain subtypes, and the vast majority of clinical cancer types and their subtypes do not have corresponding targeted drugs. In addition, with the development of clinical drug therapy, some kinases have mutated, resulting in drug resistance, and further increased the difficulty of new drug development.

In this context, the strong magnetic field center Liu Qingsong pharmacology team from scratch, constantly overcome technical difficulties, with more than four years, using mouse cells as the original template, using genetic engineering methods, targeting the current clinically common cancer-related A kinase target, a large cancer kinase cell bank that relies solely on the growth of the target gene is constructed.

The cell bank currently contains nearly 70 major kinase targets related to tumorigenesis and development, covering the vast majority of mutations associated with clinical treatment, drug resistance and prognosis found in clinical cancer patients. The cell type has reached 150. The rest. It is currently the world's largest whole-cell screening library based on kinase targets, filling the gap in such detection systems in the field of new drug creation in China. (Another cell bank of the same type is supplied by Carna Biosciences, Inc., which currently has 93 cell types).

The cell library has two characteristics. The first is that the genetic change background is single, which can more accurately and quickly indicate the mechanism of action of the drug compared with the traditional complex genetic background cancer cell line. Second, it is possible to rapidly convert various newly discovered kinase gene mutations into a single cell research model, and overcome the problems of difficulty in establishing stable cell lines, and the small amount of primary samples of patients, which cannot be further studied.

The cell bank has two major functions in drug development. The first is to test the hitting activity of the drug on the designed target, which is the most important indicator of drug efficacy. Since the cells of this library are dependent on a single kinase gene growth, if the drug affects the growth of the cell, the inhibitory activity of the drug on the target kinase can be judged. Another major function of the cell bank is to detect the target selectivity of the drug, which is an important indicator for evaluating drug side effects. Because the cell bank covers more than 70 different kinases, it can quickly determine the effect of drugs on other kinases than the target, so as to effectively evaluate the target selectivity of the drug, and the drug may be clinically toxic. Side effects are predicted.

Wang Wenchao, the main research and development staff of the cell screening library, said, "This technology system simulates clinical cancer patients at the cellular level, and is therefore called 'patients in test tubes."

The “target” is ready, followed by the development and screening of effective “bullets”. Pharmaceutical R&D personnel need to select research-producing "drug precursors" from thousands of compounds, and manual screening methods are not only time-consuming and labor-intensive, but also less accurate.

To this end, Liu Qingsong's research team established a high-throughput drug screening and testing technology platform with anti-tumor combination drug screening as the main research task in 2013. It adopts automated operating system to realize automatic liquid separation, automatic sample loading and automatic detection. A complete set of drug screening line operations can achieve the ability to complete 10,000 drug screening tests per day.

The research team also independently developed the first tumor precision treatment technology system (HDGS) that combines high-throughput targeted gene sequencing technology with high-throughput in vitro drug sensitivity detection technology. The core of the research is to use high-throughput drug screening methods. In vitro culture and high-throughput drug sensitivity testing of primary cancer cells from tumor patients, maximizing screening for available drugs for cancer patients. At the same time, the tumor-driven genes and pathogenic genes in tumor patients are detected. By comprehensively evaluating the results of gene sequencing and in vitro susceptibility testing, a precise drug-specific regimen for individual patients is proposed to achieve the goal of personalized and precise medication.

In order to allow more institutions dedicated to the development of new drugs in China to benefit from this screening system, the team relies on Zhongke Puruisheng Biomedical Technology Co., Ltd. as an industrialization promotion platform. Since the second half of 2016, it has been continuously domestically. Nearly 100 research institutes and pharmaceutical companies have provided high-quality drug testing and screening services and have gained wide industry recognition.

Source: Hefei Institute of Material Science

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