Dr. Wang Tong: Pursue the "Star Sea" of Drug Research and Development from Fragment Molecular Library

In recent years, despite the continuous emergence of new molecular type drugs, small molecule drugs are an unavoidable topic in the field of medical research and development, and they are still the main battlefield of new drug research and development. As a company dedicated to the R&D and industrialization of small molecule innovative drugs for breakthrough therapy, CGeneTech has reported many good news recently. After completing the first Sino US double reporting new drug project (CXCR4 antagonist CGT-1881) and soon starting the overseas journey, its new generation of ALK inhibitors were also approved for clinical use in the United States.

So, what are the key factors for the clinical approval of drugs? How to stand out in the field of small molecule anti-cancer, and what are the magic weapons to win a place? In the recent Mingxin Talk interview, Dr. Wang Tong, Chief Scientific Officer of CGeneTech, was invited to share the research and development strategies and trends of precise anti-cancer small molecule drugs.

Mingxinhui: Congratulate CGeneTech's CXCR4 antagonist product CGT-1881 for completing the first Sino US dual reporting new drug project and opening the overseas journey! What are the key factors for the clinical approval of this drug?

Dr. Wang Tong: The main key factors for the successful approval of CGT-1881 project include the following three aspects:

First of all, we screened appropriate small molecule compounds at the early stage of research and development, which have good activity, pharmacokinetic properties and safety. This product is currently the first clinically approved oral CXCR4 antagonist in the world, and has better medication convenience and accessibility than the marketed injectable drugs. At the same time, this product has obvious advantages in oral bioavailability and blood brain barrier crossing.

Second, our pre clinical research and development work is very solid, and we have successfully completed CMC, pharmacology, efficacy and safety experiments. Part of this work was completed with the assistance of our partner WuXi AppTec. We are very grateful to WuXi AppTec for its help in the research and development of this drug.

Finally, the communication with the regulatory authorities is also very important. Thank our application and clinical team very much. They have been communicating and coordinating with CDE and FDA teachers during the preparation of the first phase of the clinical application, overcoming various problems, and constantly making changes and adjustments. It can be said that in the first Sino US dual reporting project, the application and clinical team provided us with a good example and accumulated experience, We are confident that we will do better in the future application of new drugs.

Mingxinhui: CGeneTech has a leading integrated drug research and development technology platform in China. Can you share what technical means and strategic advantages CGeneTech has in the process of small molecule drug design and development?

Dr. Wang Tong: The biggest advantage of CGeneTech is that it has a unique fragment library. This is our CEO, Dr. Yu Qiang, who started to create it more than 20 years ago, and it has been created through the efforts of many R&D personnel, including our core team, for nearly 20 years. Our fragment molecular library is neither a commercial library nor a virtual library. This library has a real compound structure, which is excavated, screened and identified from literature, and has excellent extensibility through optimization of various synthesis work.

In addition, we have also made great efforts to the biophysical properties of these structures. We hope that small molecular fragments can have excellent pharmaceutical properties and biophysical properties. The research and development of small molecule new drugs, in addition to good activity obtained by structural combination, has a great impact on the pharmacokinetic properties and safety due to its biophysical properties. Many new drug R&D projects may be forced to stop due to poor biophysical properties in the later stage. Our small molecule fragment library has started to solve this problem in the early stage, putting the optimization of pharmacokinetic properties and safety in advance, and trying to avoid significant activity in the early stage, while problems such as pharmacokinetic properties and safety caused by biophysical properties in the later stage. Therefore, we strictly guarantee that these small molecules or lead compounds have excellent properties in all aspects at an early stage, so that they can enter the PCC stage quickly, which is our biggest feature.

At present, we are also trying to combine AI and computer technology to further screen small molecule drugs. This work has just started, and we hope to witness the real potential of this technology in the future.

Mingxinhui: What are the main aspects of precise anti-cancer drug development?

Dr. Wang Tong: Precise drug development is an important part of our innovative research and development platform. It is based on an important medical or biomedical research mechanism, which is that all tumors are driven by abnormal cell growth and loss of control caused by one or some gene mutations, not simply caused by an enzyme target or abnormal cell activity. Therefore, gene mutations are actually behind tumors. We must finally catch the culprit behind this, so that we can successfully promote an anti-cancer drug to enter the clinical or market. Precise drug research and development is actually oriented by gene mutation. All our work, from research and development to late activity and clinical trials, is centered on this.

First of all, in the early stage of R&D, when selecting targets and setting up projects, we set the goal of precision and determined the targets and R&D direction through the research and screening of gene variation. This is very important because many cancers are driven by gene variations. For example, the known mutated KRAS can promote the tumor growth of 95% of pancreatic cancer patients. In addition, KRAS gene mutations are carried by patients in skin cancer, lung cancer and other cancer types. Myc driver mutations and CCND3 driver mutations also occur in Burkitt lymphoma and other tumors. Therefore, it is very important to first identify the characteristics and directions of gene variations to determine R & D projects.

Second, in the process of new drug optimization, when we find a lead compound, we will conduct a multi-directional and accurate activity test of the compound on tumor cells to find its most effective and sensitive variation; On the other hand, we will screen a variety of mechanism compounds in R&D, and determine the R&D direction of this compound through screening of mutant genes.

Third, in the clinical stage, precision can help us determine biomarkers. Specific biomarkers are very important in clinical practice, and are an important sign to evaluate the success of clinical trials. Generally, with accurate targeted genes, we can quickly find biomarker that can be used to evaluate whether the compounds work in the clinical stage by starting with the mutated genes. We have determined the direction at an early stage to avoid clinical emergencies and improve our clinical success rate.

Mingxinhui: CGeneTech has built a wealth of innovative drug pipelines, covering many disease fields such as hypoglycemic, anti-cancer and rare diseases. What are the main considerations for this layout? What are the plans for the future?

Dr. Wang Tong: CGeneTech started from the fragment molecular library and is good at synthesis and pharmaceutical chemistry. It belongs to chemistry driven new drug research and development company. When we set up new drug research projects in all aspects, we hope to make full use of our strengths and circumvent our weaknesses.

At first, CGeneTech focused on the field of diabetes metabolism, one of its considerations was that its market was relatively large; Another consideration is that when we were researching and developing Cetagliptin, we had a small molecule library of fragments, which was a good substitute for the seedy compound or the control compound, and created our own patent space. Its activity and pharmacokinetic properties were improved. This story tells us to make full use of our fragment library and our advantages in medicine and synthetic chemistry.

We have further ploughed and laid out in the field of glucose metabolism, but the targets in this field are relatively limited. We have laid out SGLT2, GLP-1 and other targets. Although the diabetes market is huge, it has become increasingly crowded. At this time, we must consider expanding our clinical and indication directions. The tumor field covers a wide range, and now the market is further subdivided due to the emergence of precision drug therapy. From this perspective, it can reflect the advantages of our fragment molecular library, pharmaceutical chemistry and synthetic chemistry; On the other hand, I have been engaged in anti-cancer drug research in the United States for many years, so I can make better use of my previous experience to promote the development of new drugs in the cancer field of CGeneTech. Therefore, these two considerations have enabled us to break through the research and development in the field of glucose metabolism diseases and expand into the cancer field.

We are opportunists in the research and development of rare diseases. When we see an existing or relatively well understood field that has an effect on a rare disease, we will seize the opportunity to conduct pharmacological experiments. An interesting story about rare diseases. Our CGT-1881 project targets chemokine receptor 4 inhibitors, and there is a rare disease, namely the mutation of chemokine CXCR4, which leads to immune system defects in infants; This is a very characteristic defect of CXCR4 mutation, and we happen to have a CXCR4 inhibitor. It can be said that it is a coincidence that we will not miss such an opportunity.

In addition, the company also constantly updates its development direction according to the latest research and development in the biomedical field. We are also actively involved in the expansion of the field of small molecules, such as PROTAC (protein hydrolysis targeting chimeric molecules) or molecular glue (molecular glue) and other latest development directions. In addition, we also actively want to use AI to promote our research and development. For example, we can use AI's powerful functions in data to help us analyze clinical data, find better indications, and even find better ways to interpret and evaluate drugs. The company's new drug research and development is to use the latest biomedical research achievements for reference, so that our small molecule new drug research and development can take wing and fly faster and higher.

Guest introduction
Dr. Wang Tong is the Chief Scientific Officer of CGeneTech Biomedical Technology (Suzhou) Co., Ltd. (hereinafter referred to as "CGeneTech"). Dr. Wang Tong has more than 20 years of experience in full chain drug R&D and management in top pharmaceutical enterprises and research institutes in the United States. He has successively participated in and presided over nearly ten global first small molecule new drug research and development projects in pharmaceutical enterprises such as AMRI, Schering Plough, and the American Institute of Transformational Genomics/Transformational Drug Development Company, covering cancer, immunology, ophthalmology, metabolism and other disease fields. Among them, 4 projects entered the clinical stage, during which 11 papers and 4 conference reports were published, and nearly 20 patents were approved. Dr. Wang Tong is a strategic scientist who can break through key technologies, drive emerging disciplines and promote the new drug industry. After joining CGeneTech, it won the title of local science and technology leader at all levels. At the same time, it brought CGeneTech innovative thinking and advanced technical means, integrated and formed a complete new drug development and industrialization platform, and led CGeneTech's research and development team to accelerate the development of new drug product pipelines. Many new drugs in the leading product pipelines have entered the clinical and late clinical stages.