Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway.
Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway.
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DOI：
10.1038/cddis.2014.471
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发表时间：
2014-11-06
影响因子：
9
通讯作者：
Naito M
中科院分区：
文献类型：
--
作者：
Ohoka N;Nagai K;Hattori T;Okuhira K;Shibata N;Cho N;Naito M
用小分子选择性降解靶蛋白是治疗包括癌症在内的各种疾病的新方法。我们已经开发了一个蛋白质敲除系统与一系列的杂合小化合物，诱导通过泛素-蛋白酶体途径的靶蛋白的选择性降解。在这项研究中，我们设计并合成了一种名为SNIPER（TACC 3）的新型小分子，其靶向纺锤体调节蛋白转化酸性卷曲螺旋-3（TACC 3）。SNIPER（TACC 3）s诱导TACC 3的多聚泛素化和蛋白酶体降解，并降低细胞中的TACC 3蛋白水平。机制分析表明，泛素连接酶APC/CCDH 1介导SNIPER（TACC 3）诱导的TACC 3降解。有趣的是，SNIPER（TACC 3）选择性地诱导表达比正常细胞更大量的TACC 3蛋白的癌细胞的细胞死亡。这些结果表明，通过SNIPER（TACC 3）对TACC 3的蛋白质敲低是治疗过表达TACC 3蛋白的癌症的潜在策略。
The selective degradation of target proteins with small molecules is a novel approach to the treatment of various diseases, including cancer. We have developed a protein knockdown system with a series of hybrid small compounds that induce the selective degradation of target proteins via the ubiquitin–proteasome pathway. In this study, we designed and synthesized novel small molecules called SNIPER(TACC3)s, which target the spindle regulatory protein transforming acidic coiled-coil-3 (TACC3). SNIPER(TACC3)s induce poly-ubiquitylation and proteasomal degradation of TACC3 and reduce the TACC3 protein level in cells. Mechanistic analysis indicated that the ubiquitin ligase APC/CCDH1 mediates the SNIPER(TACC3)-induced degradation of TACC3. Intriguingly, SNIPER(TACC3) selectively induced cell death in cancer cells expressing a larger amount of TACC3 protein than normal cells. These results suggest that protein knockdown of TACC3 by SNIPER(TACC3) is a potential strategy for treating cancers overexpressing the TACC3 protein.
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影响因子：
30.8
作者：
通讯作者：
--
网格蛋白将磷酸化的 TACC3 招募到纺锤体极，以进行双极纺锤体组装和染色体排列
影响因子：
4
作者：
Fu, Wenxiang;Tao, Wei;Zhang, Chuanmao
通讯作者：
Zhang, Chuanmao
影响因子：
4.3
作者：
Jeng, Jen-Chong;Lin, Ying-Mei;Shih, Hsiu-Ming
通讯作者：
Shih, Hsiu-Ming
影响因子：
11.2
作者：
LeRoy, Patrick J.;Hunter, John J.;Ecsedy, Jeffrey A.
通讯作者：
Ecsedy, Jeffrey A.
影响因子：
5.3
作者：
Cappell, Kathryn M.;Sinnott, Rebecca;Whitehurst, Angelique W.
通讯作者：
Whitehurst, Angelique W.