Inhibitors of farnesyltransferase: A rational approach to cancer chemotherapy?
Inhibitors of farnesyltransferase: A rational approach to cancer chemotherapy?
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DOI：
10.1021/jm0305467
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发表时间：
2004-04-08
影响因子：
7.3
通讯作者：
Bell, IM
中科院分区：
文献类型：
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作者：
Bell, IM
尽管在过去的100年里，许多医学领域取得了重大突破，但在21世纪初，成功治疗癌症仍然是一个重大挑战。促进恶性肿瘤的分子机制的阐明正在为药物发现工作产生新的治疗靶点。其目标是生产新的药物，选择性地杀死肿瘤细胞或抑制其增殖，而没有限制传统癌症化疗的一般毒性。癌基因ras是一个被充分研究的靶点。Ras蛋白是小的GTP酶，作为开关，调节细胞功能，如增殖。1当蛋白质结合GTP时，它会被短暂激活，但通常会恢复到失活的GDP结合状态。30%的人类癌症中Ras发生突变，2，3并且突变蛋白持续结合GTP并具有组成性活性。一般认为，这种异常的功能有助于癌症的发展。1发现Ras需要异戊烯化才能发挥活性，这导致了对负责的酶法尼基转移酶（FTase）的靶向作用。因此，法尼基转移酶抑制剂（FTIs）被认为是通过抑制癌基因ras的功能来治疗癌症的合理方法。自上次在此审查以来，6种FTIs已在临床试验中显示出作为抗癌药物的疗效。与此同时，人们对Ras介导的作用机制产生了重大怀疑。
Despite major breakthroughs in many areas of medicine over the past 100 years, the successful treatment of cancer remains a significant challenge at the start of the 21st century. The elucidation of molecular mechanisms that promote malignancy is yielding new therapeutic targets for drug discovery efforts. The goal is to produce novel agents that selectively kill tumor cells or inhibit their proliferation without the general toxicity that limits traditional cancer chemotherapy. One wellstudied target is the oncogene ras. Ras proteins are small GTPases that function as on-off switches, regulating cellular functions such as proliferation. 1 When the protein binds GTP, it becomes transiently activated but normally reverts to the inactivated GDP-bound state. Ras is mutated in 30% of all human cancers, 2, 3 and the mutant proteins persistently bind GTP and are constitutively active. It is generally believed that this aberrant function contributes to the development of cancer. 1 The discovery that Ras required prenylation for activity led to the targeting of the enzyme responsible, farnesyltransferase (FTase). 4, 5 Thus, farnesyltransferase inhibitors (FTIs) were conceived as a rational way to treat cancer by inhibiting the function of the oncogene ras. Since they were last reviewed here, 6 FTIs have shown efficacy as anticancer agents in clinical trials. At the same time, significant doubt has been cast on a Ras-mediated mechanism of action.