Lead optimization and cellular targets identification of natural small-molecule STAT3 inhibitors targeting cancer stem cells
作者单位：Ministry of Education Key Laboratory of Chinese Medicinal Plants Resource from LingnanResearch Center of Medicinal Plants Resource Science and EngineeringGuangzhou University of Chinese Medicine Departments of PharmacologyShanghai Institute of Materia MedicaChinese Academy of Sciences
会议名称：《中国化学会第十二届全国天然有机化学学术会议》
会议日期：2018年
学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学]
关 键 词：Cancer stem cells Small-molecule STAT3 inhibitors Molecular probe Target identification Lead optimization
摘 要：Signal transducer and activator of transcription 3(STAT3) is an oncogene constitutively activated in many human *** activated STAT3 plays a pivotal role in holding cancer sternness in cancer stem cells,which are essential for cancer initiation,relapse,metastasis and drug ***,STAT3 has been validated as a novel anti-cancer drug target and targeting cancer stem cells considered as a novel promising therapeutic strategy to treat human *** our continuing search for novel small-molecule STAT3 inhibitors from Chinese medicinal plaints,we have previously isolated a juglone analogue KT53504 from the roots of Polygonum cuspidatum as a potent small-molecule STAT3 signaling inhibitor(IC=7.7 μM).At the present study,we designed and synthesized a biotin-conjugated probe based on the structure-activity relationship study,and then identified its direct cellular targets of lead compound using biotin chemical probe as a ***,a series of novel juglone/triazole hybrids were prepared and identified by different spectroscopic techniques,these synthesized juglone/triazole hybrids were found to significantly inhibit STAT3 signaling activities with the IC values ranging from 0.75 to48.9μ*** them,WL011101 is the most potent small-molecule STAT3 inhibitor with nanomolar level(IC=0.75μM).WL011101 exhibits good druggability and may provide a novel promising lead for developing a novel anti-cancer agent targeting cancer stem cells.