Development of small-molecule cyclin D1-ablative agents

被引:47
作者
Huang, Jui-Wen
Shiau, Chung-Wai
Yang, Jian
Wang, Da-Sheng
Chiu, Hao-Chieh
Chen, Ching-Yu
Chen, Ching-Shih
机构
[1] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA
[2] Natl Taiwan Univ, Coll Med, Dept Family Med, Taipei 10764, Taiwan
[3] Natl Hlth Res Inst, Div Gerontol Res, Taipei, Taiwan
关键词
D O I
10.1021/jm060057h
中图分类号
R914 [药物化学];
学科分类号
100701 ;
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.
引用
收藏
页码:4684 / 4689
页数:6
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