MECHANISM OF FTI ACTION AND K-RAS INHIBITION

FTI 作用和 K-RAS 抑制机制

• 批准号: 6137628
• 负责人: ADRIENNE D COX
• 金额: $ 17.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137628
• 关键词: alkyltransferase; cell transformation; enzyme inhibitors; enzyme structure; laboratory mouse; neoplastic transformation; oncogenes; protein structure function

(adapted from the investigator's abstract) Farnesyltransferase (FTase) inhibitors (FTIs) block a lipid modification critical for Ras membrane association and biological function, and easily inhibit H-Ras transforming activity in vitro and in animal models. Therefore, FTIs are under intense investigation as highly promising potential anti-cancer therapeutic agents. However, recent developments have made clear that the mechanism of FTI action is unexpectedly complex and not understood, although it certainly includes, although it certainly includes inhibition of FTase. Among the complexities are the findings that the excellent and straightforward results with H-Ras cannot be extrapolated to K-Ras; that K-Ras, the most commonly mutated form of Ras in human tumors, is highly resistant to FTI action; that FTI inhibition of transformation can be unlinked from inhibition of K-ras processing; and that Ras mutation status is not predictive for FTI sensitivity. There is general agreement that a likely explanation for some of these findings is the existence of critically important but as yet unidentified non-Ras targets of FTI action. However, both the academic and the pharmaceutic research communities are deeply divided over the significance and possible explanations for (and, therefore, of methods to overcome) the unexpectedly high resistance of K-Ras to FTIs. The existence and nature of this resistance has important implication, both for our understanding of the role and mechanism of action of the two different farnesylated Ras proteins in cellular transformation and for future successful drug design. The overall goals of this proposal are, therefore, to determine the basis for K-Ras resistance to FTI action and to determine the mechanism of FTI inhibition of transformation. To accomplish these goals, we propose to determine the relative contributions to FTI resistance of the high affinity of K-Ras for FTase and of possible alternative prenylation of K- Ras in human tumor cells; to compare the relative ability of unprocessed forms of H-, N-, and K-Ras to act as dominant negatives to block oncogenic Ras transformation; and to identify other physiologically important farnesylated targets for FTIs. The results of these experiments will provide further insight into the unexpectedly complex mechanisms of Ras processing and transformation and will provide fruitful directions for improvement in FTIs, as well as novel targets for drug design.

（改编自调查员的摘要）Farnesylsylansferase（FTase） 抑制剂（FTI）阻止了对RAS膜至关重要的脂质修饰 关联和生物学功能，并且很容易抑制H-RAS转化 体外和动物模型的活动。因此，FTI很强烈 调查是高度有希望的潜在抗癌治疗 代理商。但是，最近的事态发展明确表示 FTI动作意外复杂，尚不理解，尽管 当然包括，尽管它肯定包括对FTase的抑制。 其中的复杂性包括出色和 H-RAS的直接结果不能外推到K-RAS；那 K-Ras是人类肿瘤中最常见的RAS突变形式，高度 抵抗FTI动作； FTI对转化的抑制可能是 限制抑制K-RAS处理；和RAS突变状态 不能预测FTI敏感性。普遍同意 这些发现中的某些可能的解释是存在 至关重要但尚未确定的非RAS靶标的FTI目标 行动。但是，学术和药物研究都 社区在重要性和可能 解释（因此，克服方法）出乎意料的解释 K-Ras对FTI的高电阻。这个的存在和本质 抵抗具有重要的含义，既是我们对 两种不同的法尼式RAS的作用和作用机理 细胞转化和未来成功的药物设计中的蛋白质。 因此，该提案的总体目标是确定基础 对于K-RAS对FTI作用的抗性并确定FTI的机制 抑制转化。为了实现这些目标，我们建议 确定对高FTI电阻的相对贡献 K-RAS对FTase的亲和力和K-可能的替代前化原化的亲和力 人类肿瘤细胞中的RA；比较未经处理的相对能力 H-，N-和K-Ras的形式充当阻止致癌性的主要负面因素 RAS转换；并确定其他重要的生理重要 FTI的Farnesylation靶标。这些实验的结果将 进一步了解RAS的意外复杂机制 处理和转型将为 FTI的改进以及药物设计的新目标。