Novel small molecules are expected to resist the action of oncogenic KRAS protein
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Last Update: 2019-11-18
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Source: Internet
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Author: User
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November 19, 2019 / BIOON / -- KRAS gene mutation is considered to be the most common driver of tumor occurrence in the whole human cancer spectrum Despite its popularity, the mutated KRAS protein is still considered to be a very difficult therapeutic target; recently, an international journal Nature In the previous study report, Canon et al described a small molecule that can combine with a mutated KRAS form with high specificity and sensitivity, and inhibit the function of the protein The researchers analyzed the working mechanism of the inhibitor using an animal model, and also found that it can effectively contract tumors in patients Size, the first evidence of clinical response to a specific KRAS inhibitor KRAS is an enzyme that can control the signal pathway that is very important for cell growth, differentiation and survival The inactivated protein will combine with GDP molecule, and the replacement of GDP molecule by GTP molecule will promote the conformational change of KRAS, so as to promote the combination of enzymes and activate the downstream effectors (as shown in Figure 1a); almost all mutations of KRAS will inhibit the fragmentation of GTP, so as to One of the mutations is to use glycine residues to replace cysteine residues The mutant protein kras-g12c, which is relatively common in lung cancer, accounts for about 12% of non-small cell lung cancer Photo source: Roy S Herbst Doi: 10.1038/d41586-019-03242-8 in the past few years, researchers have developed a variety of irreversible small molecular inhibitors to covalently bind to the pocket structure of kras-g12c, which binds to GDP, so as to inhibit the binding of GTP; these inhibitors can effectively inhibit the activation of protein in animal models, but none of them can inhibit the tumor in patients To produce any effect, researcher Canon et al Studied a small molecular inhibitor named amg510, which can form covalent bond with kras-g12c, a GDP binding inhibitor Amg510 has similar structural characteristics with the former inhibitor (ars-1620), but it has a key difference, that is, it can combine with the surface groove structure formed in kras-g12c, so that it can have higher characteristics The opposite sex recognizes the mutant protein Compared with ars-1620, amg510 can more effectively inhibit the exchange of GDP and GTP In addition, amg510 can strongly inhibit the phosphorylation of ERK protein (known effector of Kars activity) in cells with kras-g12c and damage cell proliferation, the researchers said Canon and others then turned to the study of mice carrying human kras-g12c tumor cells Amg510 at a concentration of 100mg / kg can cause the tumor to subside, but then the cancer will recur However, at 200mg / kg, amg510 can cause tumors in 8 out of 10 mice There is a permanent regression; however, it is worth noting that the strong characteristics of amg510 inducing cell death increase the possibility of covalent binding with other cysteine proteins If it needs to be applied to patients regularly in the future, researchers need to further study it later What's more, only when the mice have normal immune system function can they show a lasting response to amg510 therapy with a dose of 200mg / kg; in mice without T cells, the tumor will recur, so the researchers want to know whether amg510 can be combined with anti-PD-1 immunotherapy to help regulate the immune system of patients to resist cancer; indeed When combined with anti PD-1 therapy, amg510 at a dose of 100mg / kg can make the tumor in nine out of ten mice completely subside The researchers found that amg510 therapy can enhance the expression of inflammatory molecules chemokines in animal tumors, which is related to the increased infiltration level of tumor tissue by T cells and dendritic cells, both of which can participate in the immune response of the body to cancer; later, when the researchers reintroduced kras-g12c cancer cells into mice that have been treated with combination therapy, they found that There is no tumor growth in the body; this shows that the above combined therapy can help the body to establish a long-term T cell response to kras-g12c cancer cells When amg510 therapy is combined with standard chemotherapy drugs or drugs that inhibit MEK protein, it can improve the cure rate of mice and the treatment efficiency of amg510 therapy These data may be used as amg510 clinical trials Based on the above, researcher Canon et al Described the relevant clinical research results in four patients with non-small cell lung cancer All patients carried the kras-g12c mutation and were treated with amg510 These cancer patients are a very small number of patients, and their treatment results are often promising In two of the four patients, the cancer cells in the body stopped growing The other two patients showed partial effect, that is, after 6 weeks of treatment, the tumor in vivo shrank by 34% and 67%, respectively Canon's findings are also supported by more clinical results from other research groups The researchers found that amg510 has a wide range of activities in lung cancer Among them, researchers observed tumor atrophy in 4 patients and tumor growth stop in many patients However, these data are in clinical trials In addition, when patients have tolerance to amg510 therapy, the researchers also want to know whether this combined therapy strategy can effectively treat these drug-resistant patients Researchers also want to solve other problems through research, such as whether amg510 is suitable as a first-line treatment for cancer carrying kras-g12c compared with standardized treatment involving chemotherapy or immunotherapy, and whether the new inhibitor can continue to play its role when the cancer spreads to the brain? The optimal dose of amg510 and any toxicity related to this dose need to be determined by scientists later In addition, interestingly, the researchers also want to compare the difference between this molecule and other inhibitors currently used in clinic, such as the small molecule named mrtx849 Nevertheless, the results of Canon and his colleagues provide solid evidence that amg510 therapy can lead to cancer cell death; in addition, the relevant research results also confirm the hypothesis that kras-g12c, which drives cancer, carries a special mutation, and the research also provides evidence for targeted treatment of KRAS, which does not bring KRAS inhibition into clinical practice as a key step; most importantly After that, the researchers revealed the in-depth relationship between targeted cancer therapy and the immune response of the body In-depth study of this relationship may help researchers develop new cancer combination therapy Reference materials: [1] Roy S Herbst & Joseph Schlesinger Small molecular combats cancer causing KRAS protein at last, nature 575294-295 (2019) doi: 10.1038/d41586-019-03242-8 [2] Jude canon, Karen Rex, Anne y Saiki, et al The clinical KRAS (G12C) investor AMG 510 drives anti tumour immunity, nature 575, 217–223 (2019) doi:10.1038/s41586-019-1694-1
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