THE DESIGN AND SYNTHESIS OF POTENT INHIBITORS FOR RAS FARNESYL TRANSFERASE

Ras癌基因与许多人类癌症有关。 已知存在于50%的结肠和90%以上的胰腺中 癌症。因此，ras癌基因功能的中断意味着 这是寻找抗癌药物的重要新靶点。这种蛋白质 Ras癌基因的产物是一种已知的小G蛋白p21ras。 在信号转导和细胞增殖中发挥关键作用。近期 研究表明，Ras法尼基转移酶在 RAS的法尼化及其在血浆中的定位 薄膜。由于RAS的膜结合对其 信号和转化功能，RAS法尼基转移酶代表 抗癌药物设计的新的重要靶点。此应用程序 代表了设计、合成和评估高效性的主要努力 Ras法尼基转移酶的抑制剂。 在初步结果中，我们表明在以下方面取得了重大进展 RAS法尼基转移酶模拟肽抑制剂的研究进展。 这些合成化合物中最好的在体外50到100 nm处起作用 在25微米处，破坏完整细胞的膜结合。在……里面 本申请NCDDG的化学成分(程序#1) 计划开发RAS活动地点的准确模型 法尼基转移酶，设计和合成非肽类药物 RAS法尼基转移酶，开发新型分子支架，模拟 CA/1A/2X上关键残基的位置和方向 四肽合成法呢化过渡态类似物 是法尼基转移酶的有效抑制剂的反应，以 基于机制的RAS法尼基转移酶抑制剂的设计 酶的共价修饰及其结构研究 已发现和未发现的制剂的膜透过性要求 最大化这些潜在抗癌药物的生物利用度。

The ras oncogene has been implicated in a large number of human carcinomas and is known to be present in 50% of colon and more than 90% of pancreatic cancers. Disruption of the function of the ras oncogene thus represents an important new target in the search for anti-cancer agents. The protein product from the ras oncogene is a small G-protein, p21ras, that is known to play a key role in signal transduction and cell proliferation. Recent work has shown that the enzyme Ras farnesyltransferase plays a key role in the farnesylation of Ras and its subsequent localization to the plasma membrane. Since membrane association of Ras is essential for its signaling and transforming function, Ras farnesyltransferase represents a new and important target for anti-cancer drug design. This application represents a major effort to design, synthesize and evaluate potent inhibitors of the enzyme Ras farnesyltransferase. In preliminary results we show that significant progress has been made in the development of peptidomimetic inhibitors of Ras farnesyltransferase. The best of these synthetic compounds function at 50 to 100 nM in vitro and at 25 microM in disrupting membrane association in intact cells. In the present application the Chemistry component of the NCDDG (program #1) plans to develop an accurate model of the active site of Ras farnesyltransferase, to design and synthesize non-peptide inhibitors of Ras farnesyltransferase, to develop novel molecular scaffolds that mimic the position and orientation of key residues on the CA/1 A/2X tetrapeptide, to synthesize transition state analogs of the farnesylation reaction that are potent inhibitors of the farnesyltransferase enzyme, to design mechanism based inhibitors of Ras farnesyltransferase that lead to covalent modification of the enzyme and to investigate the structural requirements of membrane permeability of the agents discovered and maximize the bioavailability of these potential anti-cancer drugs.