Sebti S M, Hamilton A D
Department of Pharmacology, University of Pittsburgh, PA 15261, USA.
Pharmacol Ther. 1997;74(1):103-14. doi: 10.1016/s0163-7258(97)00014-4.
The demonstration that Ras requires prenylation for its cancer-causing activity led several groups of investigators to an intense search for farnesyltransferase and geranylgeranyltransferase inhibitors as potential anticancer drugs. Rational design of small organic molecules that mimic the carboxyl terminal tetrapeptide prenylation site on Ras resulted in pharmacological agents capable of inhibiting Ras processing and selectively antagonizing oncogenic signaling, and suppressing human tumor growth in mouse models without side effects. These agents presently are undergoing advanced preclinical studies. This review describes the efforts of several groups to design, synthesize and evaluate the biological activities of several classes of prenyltransferase inhibitors. Several important issues, such as mechanism of action of prenyltransferase inhibitors and potential mechanisms of resistance to inhibition of K-Ras farnesylation, are also discussed.
Ras致癌活性依赖异戊二烯化的这一发现，促使多个研究小组积极寻找法尼基转移酶和香叶基香叶基转移酶抑制剂作为潜在的抗癌药物。对模仿Ras羧基末端四肽异戊二烯化位点的有机小分子进行合理设计，得到了能够抑制Ras加工、选择性拮抗致癌信号并在小鼠模型中抑制人类肿瘤生长且无副作用的药物制剂。这些制剂目前正在进行深入的临床前研究。本综述描述了多个研究小组在设计、合成和评估几类异戊二烯基转移酶抑制剂生物活性方面所做的工作。还讨论了几个重要问题，如异戊二烯基转移酶抑制剂的作用机制以及对K-Ras法尼基化抑制产生抗性的潜在机制。
