Pushing the envelope in the mTOR pathway: the second generation of inhibitors.
Pushing the envelope in the mTOR pathway: the second generation of inhibitors.
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DOI：
10.1158/1535-7163.mct-10-0905
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发表时间：
2011-03
影响因子：
5.7
通讯作者：
Tabernero J
中科院分区：
文献类型：
--
作者：
Vilar E;Perez-Garcia J;Tabernero J
磷酸二肌醇-3-激酶（PI 3 K）/哺乳动物雷帕霉素靶蛋白（mTOR）通路在过去十年中一直是癌症研究人员关注的主要焦点。对这种复杂网络的分子生物学的初步而不完全的理解不仅重要地制约了第一代mTOR抑制剂的开发，而且也制约了旨在鉴定对这些药物的最佳应答者的生物标志物研究。最近，对该途径的研究集中在mTOR的双重性质的事实上，mTOR由mTOR复合物1（mTORC 1）和复合物2（mTORC 2）整合。这两种复合物由不同的蛋白质形成和调节，也由多个不同的补偿反馈回路驱动。这种更深入的理解使得有希望的第二代抑制剂的开发成为可能，由于它们对mTOR的催化活性，它们能够同时阻断两种复合物。此外，它们中的一些还对PI 3 K产生抑制作用，PI 3 K是反馈回路中的关键参与者。本文综述了mTOR信号通路的最新研究进展，并重点介绍了mTOR抑制剂的研究进展。
The phosphatydilinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway has been a major focus of attention for cancer researchers in the past decade. A preliminary and not complete understanding of the molecular biology of this complex network has not only importantly conditioned the development of the first generation of mTOR inhibitors, but also the biomarker studies designed to identify the best responders to these agents. Most recently, research in this pathway has focused in the fact of the dual nature of mTOR that is integrated by the mTOR complex 1 (mTORC1) and complex 2 (mTORC2). These two complexes are formed and regulated by different proteins, and also driven by multiple different compensatory feedback loops. This deeper understanding has allowed the development of a promising second generation of inhibitors which are able to block simultaneously both complexes due to their catalytic activity over mTOR. Moreover, some of them also exert an inhibitory effect over PI3K that is a key player in the feedback loops. This article reviews the newest insights in the signaling of the mTOR pathway and then focuses in the development of the new wave of mTOR inhibitors.