Approaches of targeting Rho GTPases in cancer drug discovery.
Approaches of targeting Rho GTPases in cancer drug discovery.
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DOI：
10.1517/17460441.2015.1058775
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发表时间：
2015
影响因子：
6.3
通讯作者：
Zheng Y
中科院分区：
文献类型：
--
作者：
Lin Y;Zheng Y
Rho GTP酶是肌动球蛋白结构和动力学的主要调节剂，并且在包括细胞形态、基因转录、细胞周期进展和细胞粘附的多种细胞过程中发挥关键作用。由于异常的Rho GT3信号传导活性与人类癌症广泛相关，Rho GT3信号传导途径的关键组分作为潜在的治疗靶点吸引了越来越多的兴趣。与Ras类似，Rho GTP酶本身直到最近才被认为是“不可药用的”，因为结构-功能的考虑。已经探索了几种干扰Rho GT3信号传导的方法，并显示出作为对付癌细胞的新方法的前景。本文综述了RhoA、Rac 1和Cdc 42三种典型Rho GTP酶信号转导活性的研究进展。作者描述了这些Rho GTPases的参与，它们在癌症中的关键调节因子和效应因子。此外，作者讨论了目前的方法，合理地针对异常的Rho GTP酶沿着其信号级联，上游和下游的Rho GTP酶和翻译后修饰在分子水平上。迄今为止，虽然没有临床上有效的药物靶向Rho GT3信号传导用于癌症治疗，但抑制Rho GT3通路的工具化合物和先导药物已显示出前景。靶向Rho GT3信号传导的小分子抑制剂可能为未来的精确癌症治疗增加新的治疗选择，特别是与其他抗癌药物联合使用。
Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed “undruggable” because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells. This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, i.e. RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases and posttranslational modifications at a molecular level. To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents.