Identification of New Shikonin Derivatives as STAT3 Inhibitors

摘要：

　　The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design.In this study,we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold,guided by computational modelling.By tests,PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells,especially for the MDA-MB-231 cells.For the cellular mechanisms research,PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells,associated with the reduction of mitochondrial membrane potential,production of ROS and alteration of the levels of apoptosis-related proteins.Furthermore,PMMB-187 inhibited constitutive/inducible STAT3 activation,transcriptional activity,nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231.Besides,no obviously inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment.Most notably,the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth.The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.

关键词： STAT3 inhibitors Shikonin Structural modifications Anti-neoplastic Breast cancer

作者: Han-Yue Qiu Jiang-Yan Fu Min-Kai Yang Hong-Wei Han Peng-Fei Wang Ya-Han Zhang Hong-Yan Lin Cheng-Yi Tang Jin-Liang Qi Rong-Wu Yang Xiao-Ming Wang Hai-Liang Zhu Yong-Hua Yang

作者单位: State Key Laboratory of Pharmaceutical Biotechnology,NJU-NJFU Joint Institute of Plant Molecular Bio State Key Laboratory of Pharmaceutical Biotechnology,NJU-NJFU Joint Institute of Plant Molecular Bio

会议类型: 国内会议

会议名称: 第九届国际分子模拟与信息技术应用学术会议(ICMS&I2018)

会议地点: 太原

会议语种:英文

页码: 591-640

在线出版日期: 2018-05-01（万方平台首次上网日期，不代表论文的发表时间）