Targeting cell signaling pathways for drug discovery: An old lock needs a new key
Targeting cell signaling pathways for drug discovery: An old lock needs a new key
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DOI：
10.1002/jcb.21500
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发表时间：
2007-10-15
影响因子：
4
通讯作者：
Shishodia, Shishir
中科院分区：
文献类型：
--
作者：
Aggarwal, Bharat B.;Sethi, Gautam;Shishodia, Shishir
在这个靶向治疗的时代，目前大多数药物发现努力都未能产生安全，有效和廉价的药物，这引起了广泛的关注。成功的药物开发一直受到普遍关注的目标选择，而不是临床安全性和有效性的阻碍。验证靶点本身的过程效率低下，并且在许多情况下导致药物具有较差的功效和不期望的副作用。事实上，一些合理设计的药物（例如，受体酪氨酸激酶、肿瘤坏死因子（TNF）、环氧合酶-2（考克斯-2）、血管内皮生长因子（VEGF）、bcr-abl和蛋白酶体的抑制剂）对癌症和其它炎性病症无效，并产生严重的副作用。由于任何特定的癌症都携带大约300个基因的突变，这就提出了一个重要的问题，即这些靶向治疗对癌症的有效性如何。因此，有必要重新思考药物开发战略。本文分析了针对肿瘤细胞信号通路的靶向药物的不足，并对未来药物开发的可行方案进行了评价。
In this age of targeted therapy, the failure of most current drug-discovery efforts to yield safe, effective, and inexpensive drugs has generated widespread concern. Successful drug development has been stymied by a general focus on target selection rather than clinical safety and efficacy. The very process of validating the targets themselves is inefficient and in many cases leads to drugs having poor efficacy and undesirable side effects. Indeed, some rationally designed drugs (e.g., inhibitors of receptor tyrosine kinases, tumor necrosis factor (TNF), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), bcr-abl, and proteasomes) are ineffective against cancers and other inflammatory conditions and produce serious side effects. Since any given cancer carries mutations in an estimated 300 genes, this raises an important question about how effective these targeted therapies can ever be against cancer. Thus, it has become necessary to rethink drug development strategies. This review analyzes the shortcomings of rationally designed target-specific drugs against cancer cell signaling pathways and evaluates the available options for future drug development.