Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Nat Rev Cancer. 2011 Oct 24;11(11):775-91. doi: 10.1038/nrc3151.
Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming activity of many oncogenic proteins, including some RAS family members. This observation prompted the development of inhibitors of farnesyltransferase (FT) and geranylgeranyl-transferase 1 (GGT1) as potential anticancer drugs. In this Review, we discuss the mechanisms by which FT and GGT1 inhibitors (FTIs and GGTIs, respectively) affect signal transduction pathways, cell cycle progression, proliferation and cell survival. In contrast to their preclinical efficacy, only a small subset of patients responds to FTIs. Identifying tumours that depend on farnesylation for survival remains a challenge, and strategies to overcome this are discussed. One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials.
蛋白质法尼基化和香叶基化，统称为 prenylation，是脂质翻译后修饰，是许多致癌蛋白（包括一些 RAS 家族成员）转化活性所必需的。这一观察结果促使人们开发法尼基转移酶（FT）和香叶基转移酶 1（GGT1）抑制剂作为潜在的抗癌药物。在这篇综述中，我们讨论了 FT 和 GGT1 抑制剂（分别为 FTIs 和 GGTIs）如何影响信号转导途径、细胞周期进程、增殖和细胞存活的机制。与它们的临床前疗效相比，只有一小部分患者对 FTIs 有反应。确定依赖法尼基化来生存的肿瘤仍然是一个挑战，并且正在讨论克服这一挑战的策略。一种 GGTI 最近已进入临床，GGTIs 的安全性和疗效有待临床试验结果。
