國家衛生研究院 NHRI:Item 3990099045/1661
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    題名: Development of small-molecule cyclin D1-ablative agents
    作者: Huang, JW;Shiau, CW;Yang, J;Wang, DS;Chiu, HC;Chen, CY;Chen, CS
    貢獻者: Division of Gerontology Research
    摘要: Previously, we demonstrated that the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist troglitazone mediated the repression of cyclin D1 in MCF-7 breast cancer cells by facilitating proteasome-facilitated proteolysis. This PPAR gamma-independent mechanism provided a molecular basis for using troglitazone as scaffold to develop a novel class of cyclin D1-ablative agents. The proof of principle of this premise is provided by Delta 2TG, in which the introduction of a double bond adjacent to the thiazolidinedione ring abrogated the PPAR gamma activity while retaining the activity in cyclin D1 repression. Structural optimization of Delta 2TG led to STG28 [(S)-5-(4-{[6-(allyloxy)-2,5,7,8-tetramethylchroman-2-yl]methoxy}-3-methoxybenzylidene)-thiazolidine-2,4- dione], which exhibited low micromolar potency in ablating cyclin D1 and inhibiting MCF-7 cell proliferation. It is noteworthy that STG28 mediated the proteasomal degradation of cyclin D1 with a high degree of specificity. Exposure to STG28 did not cause any appreciable change in the expression levels of a series of other cyclins and CDK-dependent kinases. In light of the pivotal role of cyclin D1 in promoting tumorigenesis and drug resistance, this novel cyclin D1-ablating agent may have therapeutic relevance in cancer therapy.
    關鍵詞: Chemistry, Medicinal
    日期: 2006-07-27
    關聯: Journal of Medicinal Chemistry. 2006 Jul;49(15):4684-4689.
    Link to: http://dx.doi.org/10.1021/jm060057h
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000239141500027
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33746746418
    顯示於類別:[陳慶餘(2006-2010)] 期刊論文

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