Synthesis and biological evaluation of selective survivin inhibitors derived from the MX-106 hydroxyquinoline scaffold.
Synthesis and biological evaluation of selective survivin inhibitors derived from the MX-106 hydroxyquinoline scaffold.
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DOI：
10.1016/j.ejmech.2021.113719
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发表时间：
2021-11-15
影响因子：
6.7
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Albadari N;Deng S;Chen H;Zhao G;Yue J;Zhang S;Miller DD;Wu Z;Li W
Survivin(BIRC5)在正常分化的成人组织中表达很低，但它是肿瘤细胞中表达最广泛的基因之一。Survivin在许多癌症类型中的过度表达与化疗耐药、肿瘤转移和患者生存不良呈正相关。Survivin被认为是一种癌症特异性生物标志物，是潜在的抗癌药物靶点。在这份报告中，我们描述了一系列基于我们先前报道的先导化合物MX-106的羟基喹啉支架的新型选择性Survivin抑制剂的设计和合成。本研究中确定的最佳化合物为化合物12b。在体外，使用一组黑色素瘤、乳腺和卵巢癌细胞系，12b抑制癌细胞的增殖，平均IC50值为1.4μM。与MX-106相比，12b的代谢稳定性提高了1.7倍(人微粒体内的代谢稳定性为88min比51min)。Western印迹分析表明，12b处理选择性地降低了Survivin蛋白的水平，但对IAP家族中其他密切相关的成员的影响可以忽略不计，并强烈诱导癌细胞凋亡。在体内，当使用人类A375黑色素瘤异种移植模型进行测试时，化合物12b有效地抑制了黑色素瘤的生长。使用侵袭性原位卵巢癌小鼠模型进行的进一步评估表明，12b在抑制卵巢原发肿瘤生长和肿瘤向多个腹膜器官转移方面都非常有效。总之，本研究的结果强烈表明，以12b和我们早期的先导化合物MX-106为代表的羟基喹啉支架具有选择性靶向Survivin的能力，并有望进一步进行临床前开发。
The survivin (BIRC5) expression is very low in normal differentiated adult tissues, but it is one of the most widely upregulated genes in tumor cells. The overexpression of survivin in many cancer types has been positively correlated with resistance to chemotherapy, tumor metastasis, and poor patient survival. Survivin is considered to be a cancer specific biomarker and serves as a potential cancer drug target. In this report, we describe the design and syntheses of a series of novel selective survivin inhibitors based on the hydroxyquinoline scaffold from our previously reported lead compound MX-106. The best compound identified in this study is compound 12b. In vitro, 12b inhibited cancer cell proliferation with an average IC50 value of 1.4 μM, using a panel of melanoma, breast, and ovarian cancer cell lines. The metabolic stability of 12b improved over MX-106 by 1.7-fold (88 vs 51 min in human microsomes). Western blot analyses demonstrated that treatments with 12b selectively decreased survivin protein levels, but negligibly affected other closely related members in the IAP family proteins, and strongly induced cancer cell apoptosis. In vivo, compound 12b effectively inhibited melanoma tumor growth when tested using a human A375 melanoma xenograft model. Further evaluation using an aggressive, orthotopic ovarian cancer mouse model showed that 12b was highly efficacious in suppressing both primary tumor growth in ovaries and tumor metastasis to multiple peritoneal organs. Collectively, results in this study strongly suggest that the hydroxyquinoline scaffold, represented by 12b and our earlier lead compound MX-106, has abilities to selectively target survivin and is promising for further preclinical development.
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影响因子：
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作者：
Zhao G;Wang Q;Gu Q;Qiang W;Wei JJ;Dong P;Watari H;Li W;Yue J
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影响因子：
5.7
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