Recent patents reveal microtubules as persistent promising target for novel drug development for cancers.
Recent patents reveal microtubules as persistent promising target for novel drug development for cancers.
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DOI：
10.2174/157489109789318532
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发表时间：
2009-10
影响因子：
--
通讯作者：
U. Bughani;Shiwang Li;H. Joshi
中科院分区：
文献类型：
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作者：
U. Bughani;Shiwang Li;H. Joshi
传统上，癌症药物开发的成功靶点包括DNA损伤、复制、信号转导途径、激素、细胞因子、抗血管生成剂和放射/光敏剂。在最初的减瘤手术后，它们主宰了治疗竞技场。最近，微管蛋白，微管（MT）的主要成分，已经取得了相当成功的首次亮相，在医疗器械。微管蛋白结合药物分为两类：使微管去活化的药物和使微管过度活化并捆绑的药物。微管（MT）结合药物在某些方面是上级的性质，主要是因为他们较少衰弱的副作用相比，广义的DNA代谢靶向剂，许多新的有前途的专利正在进入药物开发管道。然而，这些相对较新的药物中的许多仍然面临与其递送方法、生物利用度、毒性以及所有化疗药物共有的不可避免的耐药性有关的挑战。最后，我们公开了一种新的抗MT药物，类诺斯卡品，刚刚开始攀登临床试验的阶梯。先导化合物诺斯卡品是一种植物衍生的、口服的、毒性最小（如果有的话）的药物，在临床前实验和I期临床试验中显示出惊人的前景。基于微管蛋白-诺斯卡品复合物的精确分子模型的合理方法必将在未来激发新的和更好的治疗类似物。
Conventionally, the successful targets for the drug development in cancer range from the DNA damage, replication, signal transduction pathways, hormones, cytokines, anti-angiogenic agents, and radio/photo-sensitizers. They dominate the therapeutic arena after the initial debulking surgery. More recently, tubulin, the primary constituent of microtubules (MTs), has made a fairly successful debut in the therapeutic armamentarium. Tubulin binding drugs come in two classes: that depolymerize microtubules and that over-polymerize and bundle them. Microtubule (MT) binding drugs are in some ways superior in nature primarily because of their less debilitating side effects when compared to the generalized DNA metabolism targeting agents, and many new promising patents are being funneled into the drug development pipeline. Nevertheless, many of these relatively new agents still face challenges relating to their delivery methods, bioavailability, toxicities, and the inevitable resistance shared by all chemotherapeutics. Finally, we disclose a new genre of anti-MT drugs, noscapinoids that have just begun climbing the clinical trials ladder. The lead compound, noscapine, is a plant derived, orally available, minimally-toxic (if at all) agent that has shown phenomenal promise in the preclinical experimentation and Phase-I clinical trial. A rational approach based upon the precise molecular model of the tubulin-noscapine complex is bound to inspire novel and better therapeutic analogs in future.