Nature: Novartis discovers "molecular glue" that kills cancer cells
Phosphatase is a class of proteins that play an important role in many cellular signaling pathways, but it is difficult for scientists to find effective small molecule compounds to inhibit their function and to develop drugs. Recently, researchers at the Novartis Institute for Biomedical Research (NIBR) designed a very novel way to limit one of the phosphatases, SHP2. They found that several compounds can "silence" or "close" their protein function. The team continues to demonstrate that this compound can kill human cancer cells in a mouse model like "molecular glue", and these positive results were published online in the June 29 issue of Nature. Researchers at NIBR are optimizing these compounds to develop new anticancer drugs for the body. Dr. Pascal Fortin, one of the authors of this paper, explained: “SHP2 performs its function just like the hinge on the door: it is only active when it is open. If it is closed, it has no function. For the first time, we have discovered such molecular prodrugs, which can bind SHP2 like 'glue' and act to inhibit the activity of SHP2 protein." Why are NIBR researchers interested in SHP2? The full name of SHP2 is called Src homology phosphotyrosyl phosphatase 2, which is located downstream of receptor tyrosine kinases such as EGFR, FGFR2, HER2 and ALK. It participates in many important signaling pathways such as MAPK to regulate cell growth. And split. SHP2 is closely related to a variety of cancers. Because of its role in many different cancers, as early as 2007, the first author of this paper, Ying-Nan Chen, proposed the concept of targeting SHP2. “In the past five years, we have gradually realized that SHP2 is more important than we thought it was,†she said. The deep understanding of SHP2 stems from a large-scale gene knockout experiment. Based on more than 390 human cancer cell lines, NIBR researchers knocked out about 7,500 genes (about one-third of the human genome) and observed cell behavior. The team found an alarming phenomenon: a decrease in the expression level of SHP2 can easily inhibit the survival of cancer cells, which means that cancer cells are very dependent on SHP2 protein activity. Given the clear therapeutic potential of SHP2 inhibitors, researchers are even more determined to find molecular candidates. But they must overcome a major obstacle: the structure of the protein. The main part responsible for SHP2 activity has a large positive charge and is relatively easy to attract negatively charged molecules. Scientists at NIBR have previously discovered several compounds that block the function of SHP2, but they all carry a negative charge. Because charged molecules are difficult to cross the cell membrane and reach their targets, this feature makes these molecular compounds difficult to become potential candidates. Travis Stams, executive director of NIBR's Proteome Chemistry Center and co-author of this article, said: "After two years of focusing on the active site of SHP2, we decided to take a step back and take a different approach. We have a hunch that may use one. A completely different way to turn off the function of this protein." The researchers then turned their attention to the different conformations of the SHP2. They realized that the active site could only be exposed when the protein was opened like a hinge. Is it possible to turn off the activity of SHP2 protein as it is "closed"? The team then designed an unconventional, multi-step chemical screening. The tamper holograms are made of advanced quality materials and adhesives. The tamper evident Hologram Labels has appealing appearance and offer security protection to the brand. Hologram Security Labels,hologram Security Sticker,One Time Use Hologram Labels,Glue Destroyable Hologram Stickers Wenzhou Haoshi Light Industrial Products Co., LTD , https://www.economicseals.com.jpg)
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