https://scholars.lib.ntu.edu.tw/handle/123456789/568504
標題: | Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity | 作者: | Chen K.-F. Tai W.-T. Hsu C.-Y. Huang J.-W. Liu C.-Y. PEI-JER CHEN Kim I. Shiau C.-W. |
關鍵字: | HCC; SHP-1; Sorafenib; STAT3 | 公開日期: | 2012 | 出版社: | Elsevier Masson SAS | 卷: | 55 | 起(迄)頁: | 220-227 | 來源出版物: | European Journal of Medicinal Chemistry | 摘要: | Previously, we demonstrated that the multiple kinase inhibitor sorafenib mediates the repression of phospho-STAT3 in hepatocellular carcinoma cells. In this study, we used this kinase-independent mechanism as a molecular basis to use sorafenib as scaffold to develop a novel class of SHP-1-activating agents. The proof of principle of this premise was provided by SC-1, which on replacement of N-methylpicolinamide by a phenylcyano group showed abolished kinase activity while retaining phospho-STAT3 repressive activity. Structural optimization of SC-1 led to compound 6, which repressed phospho-STAT3 through SHP-1 activation and inhibited PLC5 cell proliferation at sub-micromolar potency. In light of the pivotal role of phospho-STAT3 in promoting tumorigenesis and drug resistance, this novel SHP-1-activating agent may have therapeutic relevance in cancer therapy. ? 2012 Elsevier Masson SAS. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984563938&doi=10.1016%2fj.ejmech.2012.07.023&partnerID=40&md5=375eeb9386bb4486100a32aacfbd35fc https://scholars.lib.ntu.edu.tw/handle/123456789/568504 |
ISSN: | 0223-5234 | DOI: | 10.1016/j.ejmech.2012.07.023 | SDG/關鍵字: | n methylpicolinamide; phenyl group; phosphotransferase; picolinamide; protein tyrosine phosphatase SHP 1; sc 1; sorafenib; STAT3 protein; unclassified drug; animal cell; animal experiment; animal model; article; carcinogenesis; carcinoma cell; cell proliferation; cell viability; controlled study; drug potency; enzyme activation; enzyme activity; enzyme mechanism; enzyme repression; human; human cell; liver cell carcinoma; male; mouse; nonhuman; Western blotting |
顯示於: | 臨床醫學研究所 |
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