Ayral-Kaloustian Semiramis, Salaski Edward J
Wyeth Research, Pearl River, NY 10965-1299, USA.
Curr Med Chem. 2002 May;9(10):1003-32. doi: 10.2174/0929867024606687.
Specific mutations in the ras gene impair the guanosine triphophatase (GTPase) activity of Ras proteins, which play a fundamental role in the signaling cascade, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor onto cell membranes and cannot induce this transformation. Posttranslational modification and plasma membrane association of mutant Ras is necessary for this transforming activity. Since its identification, the enzyme protein farnesyltransferase (FTase) that catalyzes the first and essential step of the three Ras-processing steps has emerged as the most promising target for therapeutic intervention. FTase has been implicated as a potential target in inhibiting the prenylation of a variety of proteins, thus in controlling varied disease states (e.g. cancer, neurofibromatosis, restenosis, viral hepatitis, bone resorption, parasitic infections, corneal inflammations, and diabetes) associated with prenyl modifications of Ras and other proteins. Furthermore, it has been suggested that FTase inhibitors indirectly help in inhibiting tumors via suppression of angiogenesis and induction of apoptosis. Major milestones have been achieved with small-molecule FTase inhibitors that show efficacy without toxicity in vitro, as well as in mouse models bearing ras-dependent tumors. With the determination of the crystal structure of mammalian FTase, existent leads have been fine-tuned and new potent molecules of diverse structural classes have been designed. A few of these molecules are currently in the clinic, with at least three drug candidates in Phase II studies and one in Phase III. This article will review the progress that has been reported with FTase inhibitors in drug discovery and in the clinic.
ras基因中的特定突变会损害Ras蛋白的鸟苷三磷酸酶（GTPase）活性，而Ras蛋白在信号级联反应中起基本作用，会导致生长信号不间断，并使正常细胞转变为恶性表型。研究表明，用突变型ras基因转染的正常细胞会变成癌细胞，而未进行法尼基化的胞质突变型Ras蛋白无法锚定在细胞膜上，也无法诱导这种转变。突变型Ras的翻译后修饰和质膜结合对于这种转化活性是必需的。自其被发现以来，催化Ras加工三个步骤中的第一步也是关键步骤的酶蛋白法尼基转移酶（FTase）已成为最有前景的治疗干预靶点。FTase被认为是抑制多种蛋白质异戊二烯化的潜在靶点，从而控制与Ras和其他蛋白质的异戊二烯修饰相关的各种疾病状态（如癌症、神经纤维瘤病、再狭窄、病毒性肝炎、骨吸收、寄生虫感染、角膜炎症和糖尿病）。此外，有人提出FTase抑制剂通过抑制血管生成和诱导细胞凋亡间接帮助抑制肿瘤。小分子FTase抑制剂已取得重大进展，这些抑制剂在体外以及在携带ras依赖性肿瘤的小鼠模型中均显示出有效且无毒的效果。随着哺乳动物FTase晶体结构的确定，现有的先导化合物得到了优化，并设计了多种结构类别的新型强效分子。其中一些分子目前正在进行临床试验，至少有三种候选药物处于II期研究阶段，一种处于III期研究阶段。本文将综述FTase抑制剂在药物发现和临床应用方面的研究进展。
