Huang Jui-Wen, Shiau Chung-Wai, Yang Jian, Wang Da-Sheng, Chiu Hao-Chieh, Chen Ching-Yu, Chen Ching-Shih
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, 336 Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
J Med Chem. 2006 Jul 27;49(15):4684-9. doi: 10.1021/jm060057h.
Previously, we demonstrated that the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone mediated the repression of cyclin D1 in MCF-7 breast cancer cells by facilitating proteasome-facilitated proteolysis. This PPARgamma-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 Delta2TG, in which the introduction of a double bond adjacent to the thiazolidinedione ring abrogated the PPARgamma activity while retaining the activity in cyclin D1 repression. Structural optimization of Delta2TG 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.
此前，我们证明过过氧化物酶体增殖物激活受体γ（PPARγ）激动剂曲格列酮通过促进蛋白酶体介导的蛋白水解作用，介导MCF-7乳腺癌细胞中细胞周期蛋白D1的表达下调。这种不依赖PPARγ的机制为利用曲格列酮作为骨架开发新型细胞周期蛋白D1清除剂提供了分子基础。Δ2TG为此前提提供了原理证明，其中在噻唑烷二酮环附近引入一个双键消除了PPARγ活性，同时保留了对细胞周期蛋白D1的抑制活性。对Δ2TG进行结构优化得到了STG28 [（S）-5-（4-{[6-（烯丙氧基）-2,5,7,8-四甲基色满-2-基]甲氧基}-3-甲氧基亚苄基）噻唑烷-2,4-二酮]，它在消除细胞周期蛋白D1和抑制MCF-7细胞增殖方面表现出低微摩尔浓度的效力。值得注意的是，STG28以高度特异性介导细胞周期蛋白D1的蛋白酶体降解。暴露于STG28不会引起一系列其他细胞周期蛋白和CDK依赖性激酶表达水平的任何明显变化。鉴于细胞周期蛋白D1在促进肿瘤发生和耐药性中的关键作用，这种新型细胞周期蛋白D1清除剂可能在癌症治疗中具有治疗意义。
