THE DESIGN AND SYNTHESIS OF POTENT INHIBITORS FOR RAS FARNESYL TRANSFERASE

ras癌基因与大量的人类肿瘤有关 并且已知存在于50%的结肠和超过90%的胰腺中， 癌的 因此，ras癌基因功能的破坏代表了 一个重要的新目标，在寻找抗癌药物。 蛋白质 ras癌基因的产物是一种小G蛋白，p21 ras， 在信号传导和细胞增殖中起关键作用。 最近 研究表明，Ras法尼基转移酶在 Ras的法尼基化及其随后的血浆定位 膜的 由于Ras的膜结合对于其在细胞内的表达是必不可少的， 信号转导和转化功能，Ras法尼基转移酶代表了一种 抗癌药物设计的新的重要靶点。 本申请 代表了设计、合成和评估有效的 Ras法尼基转移酶的抑制剂。 在初步结果中，我们表明，已经取得了重大进展， Ras法尼基转移酶拟肽抑制剂的开发。 这些合成化合物中最好的化合物在50至100 nM体外发挥作用 在25 μ M时破坏完整细胞的膜结合。 在 本申请NCDDG的化学组分（程序#1） 计划开发Ras活性位点的精确模型 法尼基转移酶，设计和合成非肽抑制剂， Ras法尼基转移酶，开发新型分子支架， CA/1A/2X上关键残基的位置和方向 四肽，以合成法尼基化的过渡态类似物 反应是法尼基转移酶的有效抑制剂， 设计基于Ras法尼基转移酶抑制剂的机制， 共价修饰的酶，并研究结构 所发现试剂的膜渗透性要求， 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.