Kinase inhibitor?

In 1993, he and his colleagues developed a mouse antibody that can block VEGF and shrink tumors in mice
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This is a surprising discovery, because it is generally believed that many pathways need to be blocked to inhibit angiogenesis
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Like airplanes, tumors also have backup systems
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With these amazing results of animal experiments, Ferrara convinced the management that VEGF blockade is a feasible way to treat cancer
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Then, they began to humanize mouse antibodies, a more challenging feat
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In the end, they used a human antibody framework technology called "site-directed mutagenesis" to successfully create bevacizumab (Avastin), a human variant of anti-VEGF antibody, with 96% human antibodies and 4 % Mouse antibodies
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This recombinant humanized monoclonal antibody selectively targets VEGF and prevents it from binding to the VEGF receptor (VEGFR)
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After successful clinical trials, Avastin was approved for colorectal cancer in 2004
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Monoclonal antibodies are macromolecular biological products
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They are too large and too polar to penetrate the cell membrane
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Bevacizumab (Avastin) works by binding to VEGFR on the cell surface
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The VEGFR protein is extracellular and protrudes from the surface of the cell membrane, so it is easier to access
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On the other hand, small molecule VEGFR inhibitors can cross cell membranes, blocking VEGFR drug signal transduction and cancer cell growth
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The first small molecule VEGFR inhibitor on the market was sunitinib (Sutent), which was discovered by Sugen and later became part of Pfizer
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It is an orally active drug that exhibits strong anti-angiogenic activity by inhibiting a variety of kinases
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Specifically, sunitinib can inhibit vascular endothelial growth factor receptor (VEGFR1-3) and platelet-derived growth factor receptor (PDGFR-α-β)
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In addition, sunitinib also targets receptors involved in tumorigenesis, including fetal liver tyrosine kinase receptor 3 (Flt3) and stem cell factor receptor (c-KIT)
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Drugs with multiple target profiles are less likely to develop resistance than compounds that show selectivity for a single kinase
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In addition, drugs that act on multiple pathways at the same time may be more effective than a single targeted drug
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Sunitinib was approved by the FDA in 2006 for the treatment of gastrointestinal stromal tumors (GIST) and renal cell carcinoma (RCC) in cases where standard therapies failed
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After the advent of sunitinib, the FDA approved seven other kinase inhibitors, including Eisai's lenvatinib (Lenvima)
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In addition to a series of other kinases, they can inhibit VEGFR
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Eisai tyrosine kinase inhibitor Lenvatinib (Lenvima)

As mentioned earlier, like all cancer drugs, kinase inhibitors will encounter resistance sooner or later, so we have been fighting kinase mutations
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Therefore, there is always a need for new kinase inhibitors
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Eisai has many anti-cancer drugs, the most famous is eribulin (Halaven)
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In their kinase inhibitor project, Eisai tried to find effective angiogenesis inhibitors
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To this end, they designed an experiment for endothelial cells forming tubes, because it is important for angiogenesis and is a special phenotype of endothelial cells
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Using this experiment, they screened the Eisai compound library and obtained fragments of the quinolone skeleton containing the urea part
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The optimization of young crops eventually led to the discovery of lenvatinib (Lenvima), which is an oral receptor-type tyrosine kinase inhibitor
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It inhibits vascular endothelial growth factor receptors (VEGFRs) 1-3, fibroblast growth factor receptors (FGFRs) 1-4, and the pro-angiogenic and carcinogenic pathways related to the proto-oncogene rearrangement (RET) during transfection.
Amino acid kinase activity
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Kinase inhibitors are divided into several types (type I to type V), depending on their binding site and the conformation of the targeted kinase in its complex
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Most currently approved tyrosine kinase inhibitors are type I or type II
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However, through X-ray crystal structure analysis, it was found that lenvatinib has a new type V kinase inhibitory binding mode that is different from existing compounds
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In addition, kinetic analysis confirmed that lenvatinib can quickly bind to the target molecule and can effectively inhibit kinase activity, which may be related to its new binding mode
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After successful clinical trials, lenvatinib was granted a breakthrough treatment designation by the FDA, and lenvatinib (Lenvima) was approved for the treatment of patients with thyroid cancer in 2015
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One year later, lenvatinib was approved for the treatment of renal cell carcinoma (RCC), after having had an anti-angiogenic treatment before
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Currently, it is also approved for the treatment of hepatocellular carcinoma (HCC)
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Leo Tolstoy once said: "All happy families are similar, and each unhappy family has its own misfortune
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" Similarly, Eisai's lenvatinib has more than 60 kinase inhibitors on the market.
Many things in common
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However, it is very unique because its V-shaped binding mode makes it very special
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