Tyrosine protein kinase JAK3 has a very important significance on organ transplantation and the treatment of autoimmune diseases, which has been a potential therapeutic target. In recent years, a large number of JAK3 ...Tyrosine protein kinase JAK3 has a very important significance on organ transplantation and the treatment of autoimmune diseases, which has been a potential therapeutic target. In recent years, a large number of JAK3 inhibitors have been reported. However, the poor selectivity and side effects have limited their widespread use in clinical practice. In order to solve this problem, 52 potential small-molecule inhibitors were combined with JAK1, JAK2 and JAK3 respectively to obtain the optimal conformation of small molecules. On the basis of that we established 3D quantitative structure-activity relationships（3D-QSAR） model. Comparative molecular field analysis（Co MFA） and molecular similarity analysis（Co MSIA） were used to evaluate the model. We took advantage of reverse docking to explore the underlying toxicity and side effects. Combining 3D quantitative structure-activity relationships, surflex-dock and reverse docking results, ten 5 H-pyrrolo[2,3-b]pyrazine-2-phenyl ether derivatives based on the most optimal selectivity and activity compound 39 were designed. It can be seen from Co MFA and Co MSIA predicted active values of designed molecules that the selectivity of designed small molecules was improved obviously. Among them, compounds 61 and 62 could become the potential small molecule compounds.展开更多
Jauns激酶(jauns kinase,JAK)/信号转导子和转录活化子(signal transducer and activators of transcription,STAT)途径是一种研究多种细胞外信号能够导致特异性靶细胞上基因表达快速改变的经典途径。JAK和STAT在多种细胞分子生物学变...Jauns激酶(jauns kinase,JAK)/信号转导子和转录活化子(signal transducer and activators of transcription,STAT)途径是一种研究多种细胞外信号能够导致特异性靶细胞上基因表达快速改变的经典途径。JAK和STAT在多种细胞分子生物学变化过程中细胞因子受体信号传递中起着独特的作用。JAK/STAT途径中异常信号的传递将导致造血异常。研究表明,在多种恶性血液病中均有JAK2/STAT信号通路的异常活化,如急性淋系/髓系白血病、慢性髓系白血病、淋巴瘤、骨髓增生异常综合征、骨髓增殖性肿瘤,特别是在骨髓增殖性肿瘤(myeloproliferative neoplasm,M PN)患者中存在JAK基因突变即JAK2V617F,此突变在M PN确诊中具有重要的诊断价值。目前,JAK2特异性抑制剂疗效颇有前景,已应用于临床并取得了显著疗效。本文就JAK2/STAT信号转导,JAK2信号通路与血液病系统肿瘤及JAK2/STAT通路抑制剂进行综述。展开更多
基金supported by the Natural Science Foundation of Chongqing(cstc2015jcyjBX0080)Chongqing Research Program of Basic Research and Frontier Technology(cstc2013jcyjA10019)
文摘Tyrosine protein kinase JAK3 has a very important significance on organ transplantation and the treatment of autoimmune diseases, which has been a potential therapeutic target. In recent years, a large number of JAK3 inhibitors have been reported. However, the poor selectivity and side effects have limited their widespread use in clinical practice. In order to solve this problem, 52 potential small-molecule inhibitors were combined with JAK1, JAK2 and JAK3 respectively to obtain the optimal conformation of small molecules. On the basis of that we established 3D quantitative structure-activity relationships（3D-QSAR） model. Comparative molecular field analysis（Co MFA） and molecular similarity analysis（Co MSIA） were used to evaluate the model. We took advantage of reverse docking to explore the underlying toxicity and side effects. Combining 3D quantitative structure-activity relationships, surflex-dock and reverse docking results, ten 5 H-pyrrolo[2,3-b]pyrazine-2-phenyl ether derivatives based on the most optimal selectivity and activity compound 39 were designed. It can be seen from Co MFA and Co MSIA predicted active values of designed molecules that the selectivity of designed small molecules was improved obviously. Among them, compounds 61 and 62 could become the potential small molecule compounds.
文摘Jauns激酶(jauns kinase,JAK)/信号转导子和转录活化子(signal transducer and activators of transcription,STAT)途径是一种研究多种细胞外信号能够导致特异性靶细胞上基因表达快速改变的经典途径。JAK和STAT在多种细胞分子生物学变化过程中细胞因子受体信号传递中起着独特的作用。JAK/STAT途径中异常信号的传递将导致造血异常。研究表明,在多种恶性血液病中均有JAK2/STAT信号通路的异常活化,如急性淋系/髓系白血病、慢性髓系白血病、淋巴瘤、骨髓增生异常综合征、骨髓增殖性肿瘤,特别是在骨髓增殖性肿瘤(myeloproliferative neoplasm,M PN)患者中存在JAK基因突变即JAK2V617F,此突变在M PN确诊中具有重要的诊断价值。目前,JAK2特异性抑制剂疗效颇有前景,已应用于临床并取得了显著疗效。本文就JAK2/STAT信号转导,JAK2信号通路与血液病系统肿瘤及JAK2/STAT通路抑制剂进行综述。
