Based on a non-competitive and selective PTP1 B inhibitor reported by us previously, thirtynine benzamido derivatives were designed and synthesized as novel PTP1 B inhibitors. Among them,twelve compounds exhibited IC_...Based on a non-competitive and selective PTP1 B inhibitor reported by us previously, thirtynine benzamido derivatives were designed and synthesized as novel PTP1 B inhibitors. Among them,twelve compounds exhibited IC_(50) values at micromolar level against human recombinant PTP1 B, and most of them exhibited significant selectivity to PTP1 B over TC-PTP and CD45. Further evaluation of the most potent compound 27 on high-fat diet(HFD)-induced insulin-resistant(IR) obese mice indicated that27 could modulate glucose metabolism and ameliorate dyslipidemia simultaneously.& 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).展开更多
干扰素基因刺激因子(stimulator of interferon genes,STING)作为参与固有免疫反应的关键信号转导分子,被来自病原体和宿主的胞质DNA触发,在诱导Ⅰ型干扰素和促炎性细胞因子分泌、防御病毒及胞内细菌感染、调节体内自发性抗肿瘤免疫反...干扰素基因刺激因子(stimulator of interferon genes,STING)作为参与固有免疫反应的关键信号转导分子,被来自病原体和宿主的胞质DNA触发,在诱导Ⅰ型干扰素和促炎性细胞因子分泌、防御病毒及胞内细菌感染、调节体内自发性抗肿瘤免疫反应产生过程中发挥重要功能。STING激动剂能够有效治疗病原体感染和癌症。近10年来,对STING及其激动剂的研究发展迅速。本文从STING的结构和激活、cGAS-STING通路的机制等方面概述了STING的最新研究进展,尤其对STING激动剂进行了概述,重点分析了STING与其激动剂复合物的晶体结构以及STING激动剂的构效关系,并总结了研发STING激动剂所面临的严峻挑战,试图为设计和发现小分子STING激动剂提供思路。展开更多
基金support from the National Natural Science Foundation of China (20972192)Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-3–009)
文摘Based on a non-competitive and selective PTP1 B inhibitor reported by us previously, thirtynine benzamido derivatives were designed and synthesized as novel PTP1 B inhibitors. Among them,twelve compounds exhibited IC_(50) values at micromolar level against human recombinant PTP1 B, and most of them exhibited significant selectivity to PTP1 B over TC-PTP and CD45. Further evaluation of the most potent compound 27 on high-fat diet(HFD)-induced insulin-resistant(IR) obese mice indicated that27 could modulate glucose metabolism and ameliorate dyslipidemia simultaneously.& 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
文摘干扰素基因刺激因子(stimulator of interferon genes,STING)作为参与固有免疫反应的关键信号转导分子,被来自病原体和宿主的胞质DNA触发,在诱导Ⅰ型干扰素和促炎性细胞因子分泌、防御病毒及胞内细菌感染、调节体内自发性抗肿瘤免疫反应产生过程中发挥重要功能。STING激动剂能够有效治疗病原体感染和癌症。近10年来,对STING及其激动剂的研究发展迅速。本文从STING的结构和激活、cGAS-STING通路的机制等方面概述了STING的最新研究进展,尤其对STING激动剂进行了概述,重点分析了STING与其激动剂复合物的晶体结构以及STING激动剂的构效关系,并总结了研发STING激动剂所面临的严峻挑战,试图为设计和发现小分子STING激动剂提供思路。
