On November 11, the team of Chinese-American Wang Shaomeng published a paper titled “A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo” in the scientific journal Cancer Cell, which immediately stirred up thousands of people. Layers of waves have brought PROTAC technology back to people’s sight. Shanghai Medicilon Biopharmaceutical Co., Ltd. focuses on the development of advanced technologies and innovative drugs for customers. In recent years, our company has vigorously developed the protein degradation technology (PROTAC) platform to provide research tools for small molecules targeting the so-called non-drugable targets, in order to better help customers and assist them in the process of new drug development. Medicilon can design, synthesize (FTE and FFS two modes), optimize PROTAC molecules, establish analytical methods and finally find PCC clinical candidate compounds according to the different requirements of customers.
▲On November 11, Cancer Cell published this introduction to small molecule drugs developed using PROTAC technology
In the paper, Professor Wang’s team developed a small molecule degradation agent SD-36, which is based on PROTAC technology and can specifically degrade STAT3. This research result overcomes many problems that could not be solved before. I have a promising anti-cancer strategy. The editor below will break down this paper a bit and tell you how awesome this discovery is.
The full name of STAT3 is Signal Transducer and Activator of Transcription 3. As its name implies, it is a signal factor that conducts signals and activates transcription, and regulates the expression of intracellular proteins. In past studies, scientists have found that STAT3 plays a key role in the occurrence, progression, migration, and immune escape of cancer. That is to say, if drugs can target STAT3, it will have the potential to regulate cancer activities, inhibit or even Kill tumor cells. However, STAT3 is not an easy target. Because of its conservative structure, the specificity is not high. Therefore, no compound that can effectively and specifically inhibit STAT3 has been found.
PROTAC technology, proteolytic targeting chimera, is a bifunctional small molecule. One end of the molecule is a ligand that binds to the target protein, and the other end is a ligand that binds to E3 ubiquitin ligase, which is connected by a chain. The target protein and E3 enzyme can be brought closer in the body, so that the target protein is labeled with ubiquitin, and then degraded through the ubiquitin-proteasome pathway. In the previous articles of this public account, PROTACs have been explained in detail. Those who are interested can click the link below to learn more!
Focus on PROTAC: Make “Undruggable” Targets Drugable
▲A simple schematic diagram of the composition of PROTAC drugs
This means that the targeting function and drug killing function do not have to be realized in one compound or one structure, which reduces the threshold for compound selection. With the help of PROTAC technology, Professor Wang’s team first designed the compound SI-109 targeting the SH2 domain on STAT3, which has high affinity to the SH2 structure of STAT3 and has good cell permeability. The SH2 domain plays a key role in the dimerization of STAT3. Drugs targeting the SH2 domain can inhibit the dimerization of STAT3 and its transcriptional activity to a certain extent.
▲The SH2 binding molecule SI-109 obtained by structural optimization is combined with CRBN to obtain SD-36
On this basis, Professor Wang’s team used the factors in the E3 ligase complex designed by PROTAC to modify SD-36 and added a Cereblon (CRBN)/cullin 4A ligand to obtain a small molecule that PROTAC can degrade STAT3. drug.
The drug has a high specificity for STAT3 binding. In the experimental design of Professor Wang’s team, SD-36 and other members of the STAT family formed an experimental group, and it was found that SD-36 had no significant effect on them. Not only that, SD-36 still shows good effects in the face of mutations in the SH2 domain, so even if STAT3 has a high mutation rate, it can still be broken down by SD-36.
In animal experiments, Professor Wang’s team used the drug on leukemia model mice. The drug also showed good efficacy data. SD-36 can last and almost completely eliminate tumors.
▲SD-36 performed well in the efficacy test of animal models
The discovery of SD-36 not only provides a promising treatment plan for the treatment of cancer, but also becomes an important success case in the development of PROTAC technology, paving the way for the development of PROTAC. I believe that under the inspiration of Professor Wang, there will be more new drug discovery based on PROTAC technology, and more medical problems will be solved.
About Medicilon
Medicilon (stock code: 688202) is a drug research and development outsourcing service company (CRO) that has established a compound synthesis, compound activity screening, structural biology, pharmacodynamic evaluation, pharmacokinetic evaluation, and toxicology in Shanghai. A comprehensive technical service platform that conforms to international standards for evaluation, preparation research and new drug registration, and has been recognized by the international drug administration. Medicipua’s animal laboratory facilities have obtained AAALAC (International Association for Animal Evaluation and Certification) certification and National Medical Products Administration NMPA GLP certification, and have reached the US Food and Drug Administration GLP standard. Medicilon helps customers reach their goals faster with efficient and cost-effective one-stop professional services.
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