文章：

端粒以外靶向端粒酶的新前景

New prospects for targeting telomerase beyond the telomere

原文发布日期：2016-06-24

DOI: 10.1038/nrc.2016.55

类型: Review Article

开放获取: 否

要点：

1. Telomerase is a ribonucleoprotein complex responsible for maintaining chromosome-end structures called telomeres. Telomerase activity enables unlimited cell proliferation (immortality) in diverse human cancers.
2. Despite the cloning of the catalytic component of telomerase approximately 20 years ago and the central role of telomerase in diverse cancers, only one small-molecule telomerase inhibitor, imetelstat, has been tested in clinical trials.
3. Components of the telomerase complex have extra-telomeric activities that may contribute to cancer cell survival, proliferation and malignancy.
4. Recent advances in drug discovery technology may be leveraged in the identification and development of novel small-molecule inhibitors that simultaneously disrupt telomere maintenance and the non-canonical activities of telomerase components.
5. This Review outlines strategies for harnessing state-of-the-art drug discovery techniques to find novel cancer therapeutics that exploit multifaceted biological functions of core components of telomerase.

要点翻译：

1. 端粒酶是一种核糖核蛋白复合物，负责维持称为端粒的染色体末端结构。端粒酶活性使得多种人类癌症能够实现无限细胞增殖（永生）。
2. 尽管大约20年前已经克隆出端粒酶的催化组分，且端粒酶在多种癌症中具有核心作用，但仅有小分子端粒酶抑制剂伊美司他（imetelstat）进入了临床试验阶段。
3. 端粒酶复合物的组分具有端粒外活性，这些活性可能促进癌细胞的存活、增殖和恶性进展。
4. 药物发现技术的最新进展可用于识别和开发新型小分子抑制剂，这些抑制剂能同时破坏端粒维持功能及端粒酶组分的非经典活性。
5. 本综述概述了如何利用最先进的药物发现技术，寻找能够靶向端粒酶核心组分多重生物学功能的新型癌症疗法。

英文摘要：

Telomerase activity is responsible for the maintenance of chromosome end structures (telomeres) and cancer cell immortality in most human malignancies, making telomerase an attractive therapeutic target. The rationale for targeting components of the telomerase holoenzyme has been strengthened by accumulating evidence indicating that these molecules have extra-telomeric functions in tumour cell survival and proliferation. This Review discusses current knowledge of the biogenesis, structure and multiple functions of telomerase-associated molecules intertwined with recent advances in drug discovery approaches. We also describe the fertile ground available for the pursuit of next-generation small-molecule inhibitors of telomerase.

摘要翻译： 

端粒酶活性负责维持染色体末端结构（端粒）以及大多数人类恶性肿瘤中癌细胞的永生化，使端粒酶成为一个有吸引力的治疗靶点。越来越多的证据表明，端粒酶全酶组分在肿瘤细胞存活和增殖中具有端粒外的功能，这进一步加强了针对这些组分的合理性。本综述讨论了端粒酶相关分子的生物发生、结构和多重功能的当前知识，并结合了药物发现方法的最新进展。我们还描述了追求下一代端粒酶小分子抑制剂的广阔前景。

原文链接：

New prospects for targeting telomerase beyond the telomere