Design, Synthesis and Structure-Activity Relationship Studies of Novel Survivin Inhibitors with Potent Anti-Proliferative Properties.
Design, Synthesis and Structure-Activity Relationship Studies of Novel Survivin Inhibitors with Potent Anti-Proliferative Properties.
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DOI：
10.1371/journal.pone.0129807
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Xiao M;Wang J;Lin Z;Lu Y;Li Z;White SW;Miller DD;Li W
抗凋亡蛋白survivin在大多数人类癌细胞中高表达，而在正常分化细胞中表达极低。因此，survivin被认为是一个有吸引力的抗癌药物靶点。在此，我们报告了基于我们最近发现的hit化合物UC-112的氧喹啉支架设计和合成一系列新的生存素抑制剂。这些新的类似物针对一组癌细胞系进行了测试，其中包括一种具有多药耐药表型的癌细胞系。这些新的UC-112类似物中有8种在抗增殖实验中显示出纳米摩尔范围内的IC50值。其中最佳的3个化合物与UC-112一起提交用于NCI-60癌细胞系筛选。结果表明，从UC-112到我们的最佳化合物4g的结构修饰使活性提高了4倍（UC-112的2.2 μM比4g的0.5 μM， NCI-60面板中所有癌细胞的平均GI50值）。Western blot分析表明，与抑制凋亡蛋白家族的其他成员相比，新化合物对survivin的抑制具有较高的选择性。在A375人黑色素瘤异种移植模型中，活性最高的化合物4g在肿瘤组织中有效抑制肿瘤生长并强烈诱导癌细胞凋亡。这种新型支架有望开发选择性生存素抑制剂作为潜在的抗癌药物。
The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is considered as an attractive cancer drug target. Herein we report the design and synthesis of a series of novel survivin inhibitors based on the oxyquinoline scaffold from our recently identified hit compound UC-112. These new analogs were tested against a panel of cancer cell lines including one with multidrug-resistant phenotype. Eight of these new UC-112 analogs showed IC50 values in the nanomole range in anti-proliferative assays. The best three compounds among them along with UC-112 were submitted for NCI-60 cancer cell line screening. The results indicated that structural modification from UC-112 to our best compound 4g has improved activity by four folds (2.2 μM for UC-112 vs. 0.5 μM for 4g, average GI50 values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibition of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound 4g effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. This novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents.
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影响因子：
8.8
作者：
Leonessa, F;Green, D;Licht, T;Wright, A;WingateLegette, K;Lippman, J;Gottesman, MM;Clarke, R
通讯作者：
Clarke, R
影响因子：
2.4
作者：
Himmi, Banacer;Joly, Jean-Pierre;Sebban, Abdelfatah
通讯作者：
Sebban, Abdelfatah
影响因子：
3.6
作者：
Farruggia, Giovanna;Iotti, Stefano;Zaccheroni, Nelsi
通讯作者：
Zaccheroni, Nelsi
DOI：
10.1007/978-1-4939-2269-7_22
发表时间：
2015
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Pai, Melody Y;Lomenick, Brett;Hwang, Heejun;Schiestl, Robert;McBride, William;Loo, Joseph A;Huang, Jing
通讯作者：
Huang, Jing
影响因子：
11.2
作者：
Dong X;Mattingly CA;Tseng MT;Cho MJ;Liu Y;Adams VR;Mumper RJ
通讯作者：
Mumper RJ