Targeting tumour-supportive cellular machineries in anticancer drug development
Targeting tumour-supportive cellular machineries in anticancer drug development
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DOI：
10.1038/nrd4201
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发表时间：
2014-03-01
影响因子：
120.1
通讯作者：
Moll, Ute
中科院分区：
文献类型：
--
作者：
Dobbelstein, Matthias;Moll, Ute
传统的靶向DNA复制和细胞分裂的抗癌化学疗法有严重的副作用，但它们在治疗某些癌症方面已被证明是非常成功的。针对通过突变或过表达获得肿瘤驱动功能的信号癌蛋白的药物随后被开发出来，以增加特异性，从而减少副作用，但也有局限性，例如产生耐药性。现在，一波新的小分子抗癌药物正在出现，目标是复杂的多组分细胞机制——包括染色质修饰剂、热休克蛋白伴侣和蛋白酶体——从而干扰那些对癌细胞比正常细胞更重要的支持系统。在这里，我们提供了我们对靶向肿瘤支持细胞机制的药物的优势和局限性的观点（除了那些涉及DNA复制的药物），并将它们与靶向信号中间体的药物进行了比较。
Traditional anticancer chemotherapeutics targeting DNA replication and cell division have severe side effects, but they have proved to be highly successful in treating some cancers. Drugs targeting signalling oncoproteins that have gained tumour-driving functions through mutations or overexpression were subsequently developed to increase specificity and thus reduce side effects, but have limitations such as the development of resistance. Now, a new wave of small-molecule anticancer agents is emerging, targeting complex multicomponent cellular machineries - including chromatin modifiers, heat shock protein chaperones and the proteasome - which thus interfere with those support systems that are more essential for cancer cells than for normal cells. Here, we provide our perspective on the advantages and limitations of agents that target tumour-supportive cellular machineries (other than those involving DNA replication), comparing them with agents that target signalling intermediates.