MEK

摘要： 以齐墩果酸为先导化合物设计并合成了8个衍生物.目标产物结构通过1 H-NMR和MS确认.利用计算机辅助药物设计的方法,对目标化合物和MEK靶点进行分子对接研究.初步研究结果表明:目标产物与MEK激酶(PDB编号:4MX5)均具有高于母体化合物OA的结合能,其中化合物Ⅱ4的结合能达到-552.36 kJ/mol,值得进一步研究.

摘要： 以齐墩果酸为先导化合物设计并合成了8个衍生物.目标产物结构通过1H-NMR和MS确认.利用计算机辅助药物设计的方法,对目标化合物和MEK靶点进行分子对接研究.初步研究结果表明:目标产物与MEK激酶(PDB编号:4MX5)均具有高于母体化合物OA的结合能,其中化合物Ⅱ4的结合能达到-552.36kJ/mol,值得进一步研究.

摘要： BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.

摘要： Objective:To investigate the effect of ERK1 / 2 signaling pathway inhibitor PD98059 on Ras,Raf,MEK,ERK1,ERK2 expression in order to explore a new way for basic research and clinical treatment of the chronic mountain sickness(CMS).Methods:Sixteen CMS patients were selected,the bone marrow was collected for isolation of monomuclear cells (MNC),the cells were sorted by using CD71 and CD235a antibody magnetic beads,then positive cells were diveded into 5 groups:blank control,DMSO and PD98059 5,10 and 20 μmol/L,and were cultured in hypoxid condition for 72 hours.The Ras-GTP levels in supematant was detected by ELISA,the RT-PCR was used to determine the expression of BRaf,MEK,ERK1,ERK2 mRNA in nucleated red blood cells,and the Western blot method was used to detect expression of BRaf,MEK,ERK1,ERK2 protein.Results:PD98059 had no effect on the level of Ras-GTP in each groups.Compared with the blank control group,the expression levels of BRaf,MEK mRNA in DMSO group were not statistically significant (P values were 0.826,0.298).Compared with the PD98059 20 mol / L group,the expression level of ERK1/2 mRNA was statistically significant (P =0.001,0.002).Compared with the blank control group,expression levels of p-BRaf,p-MEK protein in DMSO group were not statistically significant (P =0.370,0.351).Compared with the PD98059 20 mol / L group,the difference of p-ERK1/2 protein level in other 4 groups were statistically significant (P values were ＜ 0.001,0.007).Conclusion:PD98059 can up-regulate the expre-ssions of ERK1/2 miRNA and p-ERK1/2 protein in bone marrow nucleated red blood cells,the Ras / Raf / MEK / ERK 1/2 pathway is the main signal transduction pathway in regulating bone marrow nucleated red blood cells,suggesting that Ras/Raf/MEK/ERK 1/2 pathway may be involved in the pathogenesis of chronic mountain sickness process.%目的:探讨ERK1/2信号通路阻断剂PD98059对Ras、B型丝/苏氨酸蛋白激酶(BRaf)、丝裂原活化蛋白激酶(MEK)、细胞信号调节激酶1/2 (ERK1/2)表达的影响,以期为慢性高原病(chronic mountain sickness,CMS)的基础研究和临床治疗探讨新的途径.方法:选取CMS患者16例,取骨髓液分离单个核细胞,以CD71与CD235a抗体磁珠分选阳性细胞,将细胞分为5组:空白对照组、DMSO溶剂组及PD98059 5、10和20 μmol/L组.在低氧条件下培养72 h,应用ELISA法测定培养骨髓有核红细胞上清液中Ras-GTP水平,RT-PCR法测定骨髓有核红细胞中BRaf、MEK、ERK1/2 mRNA的表达,Western blot方法检测骨髓有核红细胞中p-BRaf、p-MEK、p-ERK1/2蛋白表达.结果:PD98059对各组Ras-GTP的水平无明显影响(P=0.798).溶剂组与空白对照组相比,BRaf、MEK mRNA的表达水平差异无统计学意义(P =0.826、P=0.298).与PD98059 20 mol/L比较,其余4组ERK1/2 mRNA的表达水平差异有统计学意义(P =0.001、P=0.002).溶剂组与空白对照组相比,p-BRaf、p-MEK蛋白的表达差异无统计学意义(P =0.370、P=0.351).与PD98059 20 mol/L比较,其余4组p-ERK1/2蛋白水平差异有统计学意义(P ＜0.001、P＜0.007).结论:PD98059能下调骨髓有核红细胞ERK1/2 mRNA及p-ERK1/2蛋白的表达.Ras/Raf/MEK/ERK 1/2通路是调控CMS骨髓有核红细胞的主要信号传导途径,可能参与了慢性高原病的发病过程.

摘要： 基于已报道的MEK小分子抑制剂,运用Autodock 4.2研究其与MEK蛋白的作用方式,并以此设计、合成10个全新小分子化合物,其结构经1H NMR和13C NMR确定,并采用MTT法进行了体外抗肿瘤活性研究.结果表明,所设计的化合物大多对MCF-7、PANC-1、SY5Y和A549四种肿瘤细胞株有较好的作用.其中,化合物4、6、7、8、10表现了较好的活性.%This study was conducted to design and synthetize highly efficient,specific,non-resistant small MEK inhibitors.Based on active small molecules which have been reported,we studied the action mode with MEK protein using Autodock 4.2,generated innovative and feasible design method,designed novel small MEK protein inhibitors with a reference to molecular modeling and docking.The anti-tumor activities of four kinds of cells including MCF-7,PANC-1,SYSY,A549 were tested with MTT method in vitro.The structure of 10 new small molecules has been determined with 1H NMR and 13C NMR.The compounds 4,6,7,8,10 had high antitumor activities,the compounds 1,3,5 also showed good activity,and the compounds 2,9 showed cell selectivity in killing tumor.

摘要： Hepatocellular carcinoma(HCC) is a common neoplasia which represents the second leading cause of cancer related death. Most cases occur in developing countries, but its incidence is rising in Western countries due to hepatitis C. Although hepatitis therapies have evolved and the HCC screening has increased in several areas, 40% present with advanced disease which is only amenable for palliative systemic treatment. HCC continues posing a challenge, in part due to the inherent chemoresistance of this neoplasia, the pharmacologic challenges due to an ill liver, difficulty in assessing radiological responses accurately, etc. Traditional chemotherapy have shown some responses without clear survival benefit, however, sorafenib demonstrated advantages in survival in advanced HCC when liver function is kept and recently immunotherapy seems to be a promising approach for some patients. This article will briefly expose the most relevant systemic treatment modalities to offer a general view from the past to the future.

摘要： AIM To investigate the effects of herb-partitioned moxibustion(HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase(MEK)1, extracellular signal-regulated kinase(ERK)1/2 and c AMP response element binding protein(CREB) in spinal cord of rats with chronic inflammatory visceral pain(CIVP), and to explore the central mechanism of HPM in treating CIVP.METHODS Male Sprague-Dawley rats were randomized into normal, model, HPM, sham-HPM, MEK-inhibitor and dimethyl sulfoxide(DMSO) groups. The CIVP model was established using an enema mixture of trinitrobenzene sulfonic acid and ethanol. HPM was applied at bilateral Tianshu(ST25) and Qihai(CV6) acupoints in the HPM group, while in the sham-HPM group, moxa cones and herb cakes were only placed on the same points but not ignited. The MEK-inhibitor and DMSO groups received L5-L6 intrathecal injection of U0126 and 30% DMSO, respectively. Abdominal withdrawal reflex(AWR), mechanical withdrawal threshold(MWT) and thermal withdrawal latency(TWL) were applied for the assessment of pain behavior. The colonic tissue was observed under an optical microscope after hematoxylin-eosin staining. Expression of phosphor(p)MEK1, p ERK1/2 and p CREB in rat spinal cord was detected using Western blotting. The levels of MEK, ERK and CREB m RNA in rat spinal cord were detected using real-time polymerase chain reaction. RESULTS Compared with the normal group, the AWR scores were increased significantly(P < 0.01) and the MWT and TWL scores were decreased significantly(P < 0.05) in the model, sham-HPM and DMSO groups. Compared with the model group, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly in the HPM and MEK-inhibitor groups(P < 0.05). Compared with the sham-HPM and DMSO groups, the AWR scores were decreased significantly(P < 0.01) and the MWT and TWL scores were increased significantly(P < 0.05) in the HPM and MEK-inhibitor groups. Compared with the normal group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were increased significantly in the model, sham-HPM and DMSO groups(P < 0.01 or < 0.05). Compared with the model group, the expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). Compared with the sham-HPM and DMSO groups, expression of p MEK1, p ERK1/2 and p CREB proteins and the levels of MEK, ERK and CREB m RNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups(P < 0.01 or < 0.05). CONCLUSION HPM down-regulates protein phosphorylation of MEK1, ERK1/2 and CREB, and m RNA expression of MEK, ERK and CREB, inhibiting activation of the MEK/ERK/CREB signaling pathway in the spinal cord of CIVP rats, which is possibly a critical central mechanism of the analgesic effect of HPM.

摘要： 近年来，我国甲乙酮生产情况比较稳定。2015年甲乙酮产能为54．5万吨/年，产量达45万吨，产能利用率迭82．6％。未来几年我国甲乙酮新增产能较为有限。预计2016年，我国甲乙酮总产能将达到56万吨／年。

摘要： 12月20日，霍尼韦尔宣布对MEK化学公司（下称“MEK”）提起法律诉讼，指控该公司在美国境内销售的五氟丙烷（R245fa）侵犯了霍尼韦尔一项生产工艺专利权。R245fa隶属霍尼韦尔旗下英诺威。（Enovate ）品牌，是一种用于生产泡沫绝缘材料的液体发泡剂。MEK是一家总部位于美国的化学品经销商。

摘要： 公开了mTOR、MEK和PI3K的多功能抑制剂和包含该多功能抑制剂的组合物。也公开了使用多功能抑制剂治疗其中抑制mTOR、MEK和PI3K中的一种或多种提供益处的疾病和病症，如癌症的方法。

摘要： 本发明涉及用于制备6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法、用于制备结晶6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法以及适用于所述方法的中间体。本文还提供包含此结晶化合物的药物组合物。

摘要： 本发明涉及用于制备6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法、用于制备结晶6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法以及适用于所述方法的中间体。本文还提供包含此结晶化合物的药物组合物。

摘要： 提供了具有突变型MEK序列的核酸和蛋白质，和涉及鉴定对于用抗癌剂特别是RAF或MEK的抑制剂的治疗具有抗性的患者的方法。还提供了治疗和用于最佳化用于在MEK1序列中具有突变的患者的治疗的方法。

摘要： 公开了mTOR、MEK、JAK和PI3K的抑制剂以及包含它们的组合物。还公开了使用所述抑制剂治疗多种疾病和病症的方法，其中mTOR、MEK、JAK和PI3K中的一种或多种的抑制提供益处。还公开了使用化学连接部分和接头改变化合物溶解度和/或淋巴吸收的方法。

摘要： 本发明涉及用于制备6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法、用于制备结晶6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法以及适用于所述方法的中间体。本文还提供包含此结晶化合物的药物组合物。

摘要： 公开了mTOR、MEK和PI3K的多功能抑制剂和包含该多功能抑制剂的组合物。也公开了使用多功能抑制剂治疗其中抑制mTOR、MEK和PI3K中的一种或多种提供益处的疾病和病症，如癌症的方法。

摘要： 本发明涉及用于制备6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法、用于制备结晶6‑(4‑溴‑2‑氟苯基氨基)‑7‑氟‑3‑甲基‑3H‑苯并咪唑‑5‑甲酸(2‑羟基乙氧基)‑酰胺的方法以及适用于所述方法的中间体。本文还提供包含此结晶化合物的药物组合物。

摘要： 本发明涉及用于制备6-(4-溴-2-氟苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-甲酸(2-羟基乙氧基)-酰胺的方法、用于制备结晶6-(4-溴-2-氟苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-甲酸(2-羟基乙氧基)-酰胺的方法以及适用于所述方法的中间体。本文还提供包含此结晶化合物的药物组合物。

摘要： 本发明提供了具有突变型MEK序列的核酸和蛋白质，和涉及鉴定对于用抗癌剂特别是RAF或MEK的抑制剂的治疗具有抗性的患者的方法。还提供了治疗和用于最佳化用于在MEK1序列中具有突变的患者的治疗的方法。