Yoshimatsu K
Tsukuba Research Laboratories, Eisai Co., Ltd.
Gan To Kagaku Ryoho. 1997 Sep;24(11):1495-502.
Posttranslational modification and membrane localization are critical for the function of products of ras oncogenes which are frequently founded to be mutated in human tumors. Farnesylation by farnesyltransferase (FTase) is the first and obligatory step in the processing of ras p21, and FTase has attracted attention as a new target of anticancer agents. Many FTase inhibitors have been identified or synthesized in random screening, and studies on FPP analogs, CAAX analogs, and bisubstrate analogs. These inhibitors induced flat reversion and inhibited the anchorage-independent growth of ras transformant and ras-mutated human tumor cells through the inhibition of posttranslational modification of ras p21. B1086, L-739,749, L-744,832 and FTI-276, which are CAAX analogs, were reported to show inhibition of tumor growth in ras-mutated human tumor xenograft models and to induce regression of mammary and salivary carcinoma in ras transgenic mouse model. FTase inhibitors have the potential to be developed as therapy for ras-mutated human tumors. On the other hand, it has been reported that K-ras 4B p21 could be modified by geranylgeranyltransferase (GGTase). Therefore, GGTase inhibitors have also been evaluated in addition to FTase inhibitors.
翻译后修饰和膜定位对于ras癌基因产物的功能至关重要，而ras癌基因在人类肿瘤中经常发生突变。法尼基转移酶（FTase）介导的法尼基化是ras p21加工过程中的第一步且是必需步骤，并且FTase作为抗癌药物的新靶点已引起关注。在随机筛选中已鉴定或合成了许多FTase抑制剂，并对法尼基焦磷酸（FPP）类似物、CAAX类似物和双底物类似物进行了研究。这些抑制剂诱导扁平逆转，并通过抑制ras p21的翻译后修饰来抑制ras转化细胞和ras突变的人类肿瘤细胞的非锚定依赖性生长。据报道，作为CAAX类似物的B1086、L-739,749、L-744,832和FTI-276在ras突变的人类肿瘤异种移植模型中显示出对肿瘤生长的抑制作用，并在ras转基因小鼠模型中诱导乳腺癌和唾液腺癌消退。FTase抑制剂有潜力被开发用于治疗ras突变的人类肿瘤。另一方面，据报道K-ras 4B p21可被香叶基香叶基转移酶（GGTase）修饰。因此，除了FTase抑制剂外，GGTase抑制剂也已得到评估。
