[Inhibitors of farnesyl transferase in oncology: from basic research to pharmaceutical research].

F Lavelle
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Abstract

Advances in medical oncology have been obtained with compounds having new structure/mechanism of action. Pharmaceutical research is largely focused on "prospective" targets identified by basic science such as the oncogenic signal transduction pathways. Ras proteins stand as converging targets that could be blocked by different approaches including inhibition of the isoprenylation of the proteins. Many academic institutions and pharmaceutical companies have embarked on the research of farnesyl transferase inhibitors. Two approaches have been developed: 1) random screening of compounds from natural/synthetic origin; 2) synthesis of compounds able to mimic the C-terminal tetrapeptidic "CAAX box" and to inhibit consequently the critical step of farnesylation. This peptidomimetic approach has been successfull since active and specific inhibitors of Ras proteins farnesylation have been synthesized in the nM range. However, several major drawbacks have been identified: in particular, most of the time, the preclinical evaluation has been done with biochemical and biological materials implicating the activated Ha-ras oncogene (very unfrequently activated in human tumors) instead of the activated Ki-ras oncogene which is the relevant target in human carcinomas. This has resulted in the selection of compounds with preferential activity on Ha-ras tumors. Nevertheless, evidence has been now generated that inhibition of farnesyl transferase of ras proteins can lead to significant experimental antitumor effects. The most convincing data are those obtained with the Merck inhibitor L739,749 which is able to cause tumor regressions of carcinomas in transgenic mice.

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[法尼基转移酶抑制剂在肿瘤学中的应用:从基础研究到药物研究]。
具有新结构/作用机制的化合物在肿瘤医学领域取得了进展。药物研究主要集中在基础科学确定的“前瞻性”靶点,如致癌信号转导途径。Ras蛋白作为会聚靶点,可以通过不同的方法来阻断,包括抑制蛋白质的异戊二烯化。许多学术机构和制药公司已经开始了法尼基转移酶抑制剂的研究。目前已经开发了两种方法:1)随机筛选天然/合成来源的化合物;2)合成能够模拟c端四肽“CAAX盒”的化合物,从而抑制法尼化的关键步骤。这种拟肽方法是成功的,因为在nM范围内已经合成了Ras蛋白法尼化的活性和特异性抑制剂。然而,已经确定了几个主要的缺点:特别是,大多数时候,临床前评估是用生化和生物材料进行的,这些材料涉及活化的Ha-ras癌基因(在人类肿瘤中很少被激活),而不是活化的Ki-ras癌基因,后者是人类癌症的相关靶点。这导致了对Ha-ras肿瘤具有优先活性的化合物的选择。然而,现在已经有证据表明,抑制ras蛋白的法尼基转移酶可以导致显著的实验性抗肿瘤作用。最令人信服的数据是默克公司的抑制剂L739,749获得的,它能够在转基因小鼠中引起癌症的肿瘤消退。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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