Ohkanda Junko, Knowles David B, Blaskovich Michelle A, Sebti Said M, Hamilton Andrew D
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
Curr Top Med Chem. 2002 Mar;2(3):303-23. doi: 10.2174/1568026023394281.
This paper describes recent progress in the design, synthesis and biological evaluation of inhibitors for the enzyme protein farnesyltransferase (PFTase). This enzyme plays a critical role in the post-translational modification of a range of different intracellular proteins. In particular, PFTase attaches a farnesyl group to the GTPase Ras whose oncogenically mutated form is found in over 30% of human cancers. As a result PFTase inhibitors have been developed as potential cancer therapeutic drugs either by rational design based on the structure of the CAAX carboxyl terminus of Ras or random screening of chemical libraries or natural products. Some of these inhibitors show remarkable inhibition potency against PFTase at subnanomolar concentrations and >1000-fold selectivity compared to the related enzyme geranylgeranyltransferase-I. Certain of these compounds are highly effective at blocking the growth of human tumors in animal models and are now undergoing clinical trials. However, several issues in the research remain unsolved, including the mechanism by which PFTase inhibitors suppress tumor growth. Although it has been established that PFTase inhibitors block prenylation of Ras in vitro, the results in wholecells and animal studies suggest the possibility that proteins other than Ras are affected.
本文描述了法尼基转移酶（PFTase）抑制剂在设计、合成及生物学评价方面的最新进展。该酶在多种不同细胞内蛋白质的翻译后修饰过程中发挥关键作用。特别是，PFTase会将一个法尼基基团连接到GTP酶Ras上，超过30%的人类癌症中都存在Ras的致癌突变形式。因此，基于Ras的CAAX羧基末端结构进行合理设计、对化学文库或天然产物进行随机筛选，都开发出了PFTase抑制剂作为潜在的癌症治疗药物。其中一些抑制剂在亚纳摩尔浓度下对PFTase表现出显著的抑制效力，与相关酶香叶基香叶基转移酶-I相比具有>1000倍的选择性。某些此类化合物在动物模型中能高效阻断人类肿瘤的生长，目前正在进行临床试验。然而，该研究中的几个问题仍未解决，包括PFTase抑制剂抑制肿瘤生长的机制。尽管已经确定PFTase抑制剂在体外可阻断Ras的异戊二烯化，但全细胞和动物研究结果表明，除Ras外的其他蛋白质也有可能受到影响。
