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首页> 外文期刊>Expert opinion on therapeutic targets >Not the comfy chair! Cancer drugs that act against multiple active sites
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Not the comfy chair! Cancer drugs that act against multiple active sites

机译：不是舒适的椅子！ 癌症药物对多个活性位点起作用

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ABSTRACT Introduction: Discoveries of novel signal transduction pathways in the 1990s stimulated drug companies to develop small molecule tyrosine kinase and serine / threonine kinase inhibitors which were based on catalytic site inhibition. All kinases bind ATP and catalyze phosphate transfer and, therefore, inhibitors that block ATP binding and its metabolism would be predicted to have a known on-target specificity but were also likely to have many unknown or unrecognized targets due to similarities in all ATP binding pockets. This on-target off-target biology of kinase inhibitors, which exhibit a "signal" in the clinic, means that therapeutically valuable agents are acting through unknown biological processes to mediate their anti-tumor effects. Areas covered: This perspective discusses drug therapies whose actions cannot be explained by their actions on the original targeted kinase; it concludes with a methodology to screen for changes in cell signaling via in-cell western immunoblotting. Expert opinion: Most malignancies do not depend on survival signaling from one specific mutated proto-oncogene, especially for previously treated malignancies where multiple clonal variants of the primary tumor have evolved. Hence, the concept of a highly "personalized medicine" approach fails because it is unlikely that a specific therapy will kill all clonal variants of the tumor.
机译：摘要介绍：在20世纪90年代的新型信号转导途径发现刺激药物公司开发基于催化位点抑制的小分子酪氨酸激酶和丝氨酸/苏氨酸激酶抑制剂。所有激酶均结合ATP并催化磷酸盐转移，因此预测嵌段嵌段嵌段及其代谢的抑制剂具有已知的靶标特异性，但由于所有ATP绑定口袋中的相似性也可能具有许多未知或无法识别的靶标。这种在临床中表现出“信号”的激酶抑制剂的靶标脱靶生物学意味着治疗性有价值的药剂通过未知的生物方法作用以介导其抗肿瘤作用。所涵盖的区域：这种观点讨论了药物治疗，其行为不能通过原始靶向激酶的作用解释;通过筛选通过细胞内免疫印迹的细胞信号传导变化的方法结束。专家意见：大多数恶性肿瘤不依赖于一种特异性突变的原癌基因的存活信号，特别是对于先前治疗的恶性肿瘤，其中原发性肿瘤的多个克隆变体已经发展。因此，高度“个性化医学”方法的概念失败，因为特定治疗不太可能会杀死肿瘤的所有克隆变体。

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