Signaling through Rho GTPase pathway as viable drug target.
Signaling through Rho GTPase pathway as viable drug target.
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DOI：
10.2174/092986709787846569
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发表时间：
2009
影响因子：
4.1
通讯作者：
Chen YH
中科院分区：
文献类型：
--
作者：
Lu Q;Longo FM;Zhou H;Massa SM;Chen YH
通过Rho家族的小GTP酶的信号转导已经越来越多地被研究，因为它们参与各种各样的疾病，如心血管疾病、肺疾病和神经疾病以及癌症。Rho GTP酶是Ras超家族蛋白的一个亚家族，在许多生物学过程中发挥重要作用，特别是在调节细胞形状变化、胞质分裂、细胞粘附和细胞迁移中。这些过程中的许多表现出一个共同的主题：肌动蛋白细胞骨架的快速和动态重组，其中Rho信号转导现已成为一个主要的开关控制。Rho GTP酶在疾病状态中的动态变化的参与强调了产生用于其治疗应用的有效抑制剂的需要。法舒地尔和Y-27632是两类广泛使用的抑制Rho激酶（ROCK）的化合物，其中Rho激酶是RhoA亚家族GTP酶的重要下游效应子。这些抑制剂已在许多临床前研究中获得成功，表明临床Rho通路抑制的潜在益处。另一方面，除了Rac1抑制剂NSC23766之外，几乎没有直接靶向Rho GTP酶的有效抑制剂，这可能是由于缺乏关于单个Rho-RhoGEF、Rho-RhoGAP或Rho-RhoGDI相互作用的最佳结构信息以实现特异性。最近，LM11A-31和p75促神经生长素受体（p75NTR）的肽模拟配体的其他衍生物显示出在神经元再生中Rho GT3信号传导上游的有希望的作用。CCG-1423是一种具有RhoA下游抑制作用的化合物，是开发新的药理学工具来破坏癌症中Rho信号通路的进一步尝试。由于越来越多的研究揭示了Rho蛋白在许多疾病中的作用，因此迫切需要Rho GT3信号通路各个步骤的特异性和有效的药物调节剂，以靶向心血管疾病、神经障碍和癌症进展的治疗干预。
Signaling through the Rho family of small GTPases has been increasingly investigated for their involvement in a wide variety of diseases such as cardiovascular, pulmonary, and neurological disorders as well as cancer. Rho GTPases are a subfamily of the Ras superfamily proteins which play essential roles in a number of biological processes, especially in the regulation of cell shape change, cytokinesis, cell adhesion, and cell migration. Many of these processes demonstrate a common theme: the rapid and dynamic reorganization of actin cytoskeleton of which Rho signaling has now emerged as a major switch control. The involvement of dynamic changes of Rho GTPases in disease states underscores the need to produce effective inhibitors for their therapeutic applications. Fasudil and Y-27632, with many newer additions, are two classes of widely used chemical compounds that inhibit Rho kinase (ROCK), an important downstream effector of RhoA subfamily GTPases. These inhibitors have been successful in many preclinical studies, indicating the potential benefit of clinical Rho pathway inhibition. On the other hand, except for Rac1 inhibitor NSC23766, there are few effective inhibitors directly targeting Rho GTPases, likely due to the lack of optimal structural information on individual Rho-RhoGEF, Rho-RhoGAP, or Rho-RhoGDI interaction to achieve specificity. Recently, LM11A-31 and other derivatives of peptide mimetic ligands for p75 neutrotrophoin receptor (p75NTR) show promising effects upstream of Rho GTPase signaling in neuronal regeneration. CCG-1423, a chemical compound showing profiles of inhibiting downstream of RhoA, is a further attempt for the development of novel pharmacological tools to disrupt Rho signaling pathway in cancer. Because of a rapidly growing number of studies deciphering the role of the Rho proteins in many diseases, specific and potent pharmaceutical modulators of various steps of Rho GTPase signaling pathway are critically needed to target for therapeutic intervention in cardiovascular disease, neurological disorders, and cancer progression.
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影响因子：
4.2
作者：
Brabeck, C;Beschorner, R;Schwab, JM
通讯作者：
Schwab, JM
影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1111/j.1440-1681.2008.05045.x
发表时间：
2009-03-01
影响因子：
2.9
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
5.7
作者：
Breitenlechner, C;Gassel, M;Bossemeyer, D
通讯作者：
Bossemeyer, D