1. How do multinational pharmaceutical companies solve the problem of low return on investment?
In 2017, GSK shut down Shanghai Zhangjiang's neurological disease research and development center; Lilly Pharmaceuticals closed Shanghai Zhangjiang's China R&D center;
In 2016, Novartis closed the cell and gene therapy division;
In 2015, Aberdeen closed the Kidney Disease Research Center.
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Compared with the prosperity of multinational pharmaceutical companies in the past 15 years to establish R&D centers in China, in recent years, multinational pharmaceutical companies have greatly reduced or even closed their R&D centers and investment resources in China, which makes people worry about the prospects of new drug research and development.
According to a report released by Deloitte in December 2017, the return on investment for new drug research and development in 2017 was only 3.2%, and the cost of listing a new drug was as high as $1.99 billion.
In addition to huge research and development investment, when the new drug is launched, the initial patent protection period of the compound is also very low. The patent protection period that can be seen at the bottom does not even support the peak of new drug sales, and it faces the siege and patent challenge of generic drugs.
Under the premise of ensuring the quality of new drugs, how to shorten the research and development cycle and improve the success rate has become a topic of concern for all pharmaceutical people. Whether it is cooperative research and development, IP-VC-CRO, overall outsourcing and other models, or in-depth research on targets, improve screening techniques and other means, scientists are actively trying.
In June 2018, AstraZeneca scientists counted 66 new drug development articles published in the Journal of Medicinal Chemistry from 2016 to 2017 to explore commonly used drug discovery strategies, summarizing five commonly used techniques, including based on known structures. Derivative methods for compounds, random high-throughput screening, structure-based drug design, fragment-based lead compound discovery, and DNA-coding compound library screening. Among them, the DNA coding compound library technology is one of the emerging technologies in the research and development of new drugs. It has achieved great development in the past few years and is favored by large pharmaceutical companies and investors at home and abroad.
It has been reported that AstraZeneca has stated that the use of DEL technology is one of the reasons for the improvement of its research and development productivity.
Analysis of DNA coding compound library technology related literature collected by PubMed database from July to July 2018. In academia and industry, the research and application of DNA coding compound library technology has been on the rise since 2012, many based on DEL. The development of new drug developments in technology, large-scale transaction cooperation, and companies engaged in DNA-coded compound libraries have also emerged intensively since this time. Large-scale cooperative transactions such as Sanofi and DICE contracted a total of $2.3 billion in new drug research and development cooperation.
Literature Classification Based on DNA-Coded Compound Library Technology in Pubmed in 1992-2018
According to further statistics, 19 of the top 20 global pharmaceutical companies (ranked by 2016 sales) use DNA coding compound library technology to develop new drug development through external cooperation or internal research and development.
2. DNA coding compound library technology empowers new drug development
The traditional compound library is limited by the high synthesis cost of the compound, the large storage space requirement, the strict screening requirements and the high degree of automation requirements. The capacity of the compound library available for screening is often in the order of one million. An important condition for the discovery of lead compounds is the need for a sufficient number of compounds to be screened. Large compound libraries often require decades of accumulation and substantial ongoing capital investment. For companies that are committed to new drug development in China, it is not optimal to build a multi-million-level compound library using conventional methods. But the scientists' pursuit of a larger chemical space has never stopped, and they have gathered their attention in the field of DNA-coded compound library technology.
The discovery of RIP1 inhibitors is a typical example of the application of DNA-encoding compounds.
At the beginning of the project, GlaxoSmithKline scientist Harris et al. used a fluorescence polarization screening method to screen a kinase library containing 40,000 compounds, and used a high-throughput screening technique to screen a library containing 2 million compounds. Lead compound. Finally, 7.7 billion compounds were screened by DNA-encoding compound library technology, and GSK481, a target compound that specifically binds to the RIP1 target and efficiently blocks TNF-dependent cellular pathways, was obtained in one go. In the subsequent optimization process, only the two atoms on the heterocycle were modified and directly entered the clinic. Currently, the compound is in phase II clinical study.
Compared with the traditional technology, the DNA coding compound library can not only reach a wider chemical space, but the requirements for reagents, hardware facilities and the like are relatively easier to implement, and the synthesis and screening costs are significantly reduced.
Compared with traditional technology, DEL technology not only has advantages in screening compound quantity and cost, but also has advantages in screening efficiency and time.
It usually takes only a few weeks to synthesize a library of DNA-coding compounds, and it takes only a few months to screen a billion-dollar compound, which greatly shortens the cycle of discovery of new drugs. In addition, the technology can quickly and efficiently discover new structural compounds against mature targets, avoiding low levels of duplication; targeting traditionally considered small molecule drug-making targets can screen for target compounds, such as PPI-like targets, IL17 targets; The target can efficiently find the StartingPoint, which provides the possibility to quickly carry out subsequent research to seize the opportunities in this field.
DNA-encoding compound library technology enables screening of traditional targets, challenging targets and emerging targets and successful production of high-quality target compounds
Med.Chem.Commun.,2016,7,1898-1909
3. China's strategy to cope with the crisis of new drug research and development
The DNA-encoding compound library technology is a multidisciplinary and highly integrated technology platform. At present, X-Chem, Nuevolution and HitGen (Chengdu Pilot), which are capable of providing large-scale research and development of new drugs based on DNA-encoded compound libraries, are available worldwide.
Among them, as the first biotechnology company in China to develop new drugs based on DNA-encoded compound library technology, since 2015, the company has disclosed 22 new drug research and development partners, including many of them expanding cooperation with Pfizer and Merck.
Globally, according to the incomplete statistics of public data of various companies' websites, the number of new drug research and development cooperation based on DNA-coded compound library technology has been 64 in the world since 2015, and the number of Chengdu-leading cooperation accounts for 34.4%. X-Chem 25% of the total, Denmark Nuevolution accounted for 12.5%.
2015-2018 Cooperative distribution of globally published DNA-based compound library technology
(Total number of global public transactions: 64)
DNA-encoding compound library technology can screen for high-quality lead compounds that other technologies may miss for a certain disease mechanism, ensuring the breadth of screening and improving the efficiency of screening. It is a biotechnology company or a transformational biotechnology company in China that is committed to new drug development. Traditional pharmaceutical companies have provided new solutions for the deployment of new drugs at low cost and high efficiency in the layout of hot targets or emerging targets.
4. Conclusion: Innovation leads the future
The fundamental purpose of new drug research and development is to continuously find new molecular entities that can effectively regulate disease targets in diseases that do not meet the therapeutic needs. Although in the long struggle against disease, human beings have successfully converted many malignant diseases into chronic diseases, many chronic diseases have been cured, but this war is far from over, and more "stubborn" diseases have been discovered and become affected with the development of science and technology. A new threat to the quality of human life.
In the face of new challenges, innovation is imperative.
As the title has raised, 19 of the top 20 pharmaceutical companies in the world have chosen to use DNA-encoded compound library technology to lay out new drug developments. On the one hand, they prove the great potential of this technology in the development of new drugs, on the other hand, it is also pointed out in the severe In the face of challenges, even multinational pharmaceutical companies, using innovative technologies for new drug research and development is an important means to quickly achieve corporate strategic goals.
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