Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth
Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth
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DOI：
10.1021/acs.jmedchem.6b00463
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发表时间：
2016-10-13
影响因子：
7.3
通讯作者：
Liekens, Sandra
中科院分区：
文献类型：
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作者：
Jesus Perez-Perez, Maria;Priego, Eva-Maria;Liekens, Sandra
肿瘤血管系统的独特特征提供了使用微管蛋白去稳定剂选择性靶向肿瘤生长和血管形成的可能性。与考布他汀A-4（CA-4）及其前药CA-4P积累的证据支持化合物共享该作用机制的治疗价值。然而，CA-4的化学不稳定性和溶解性差需要能够克服这些限制的替代化合物。该观点说明了不同类别的化合物，其行为类似于CA-4，根据最近可用的结构复合物分析其与α β-微管蛋白的结合模式，并包括所述的方法来改善其递送。此外，解剖CA-4和类似物的作用机制允许更深入地了解与这些作为血管破坏剂（VDA）的微管蛋白去稳定剂相关的优点和缺点。
The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapentic value of compound's sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to alpha beta-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the, advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).