TARGET-GUIDED DEVELOPMENT OF SPECIFIC AKT INHIBITORS

特定 AKT 抑制剂的靶向开发

• 批准号: 7125414
• 负责人: HARTMUTH C KOLB
• 金额: $ 27.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125414
• 关键词: adenosine triphosphate; antineoplastics; chemical structure function; combinatorial chemistry; computational biology; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; enzyme structure; kinase inhibitor; neoplastic transformation; serine threonine protein kinase

DESCRIPTION (provided by applicant): We plan to produce highly specific and potent inhibitors of the Akt kinase using in situ click chemistry, a new technique that employs the target protein for assembling inhibitors from simple precursors. Akt is a serinethreonine protein kinase that plays a central role in the control of cell growth and replication. It shows a gain of function in about 50 percent of the non-small cell lung cancers. Cancer of the breast, prostate and pancreas also show involvement of Akt. The potential clinical indications for Akt inhibitors are, therefore, wide and numerous. In situ click chemistry allows the generation of biligand inhibitors of unsurpassed specificity and potency for Akt. The principle of this method is to design two ligands targeted to two neighboring sites on the enzyme. The ligands are equipped with complementary reactive groups, and upon simultaneous binding of the two ligands to their targets, these reactive groups form a covalent connection, causing the formation of a biligand, which engages in multiple interactions with the protein's binding pockets. The specific aims are: (1) Design and produce libraries of compounds that are targeted at the ATP-binding site and that carry additional functional groups for in situ click chemistry; screen these libraries in vitro for ATP-competitive Akt inhibitors that will be used as anchor molecules. (2) Perform in situ click chemistry with anchor molecules bound to Akt and generate bivalent Akt ligands. (3) Determine potency and specificity of bivalent Akt inhibitors, perform cell-based assays for interference with Akt-induced oncogenic transformation. (4) Investigate the structure-activity relationship through in situ click chemistry and optimize inhibitors for potency, selectivity and cell-based activity

描述（由申请人提供）：我们计划使用SICK CHICK CHEMICTER生成Akt激酶的高度特异性和有效的抑制剂，这是一种新技术，该技术采用靶蛋白来从简单的前体组装抑制剂。 AKT是一种血清素蛋白蛋白激酶，在控制细胞生长和复制中起着核心作用。它显示了大约50％的非小细胞肺癌的功能增长。乳腺癌，前列腺和胰腺的癌症也显示出AKT的参与。因此，AKT抑制剂的潜在临床适应症是广泛而众多的。原位点击化学允许生成Akt无与伦比的特异性和效力的双质抑制剂。该方法的原理是设计两个针对酶上两个相邻位点的配体。配体配备了互补的反应基团，并且在两个配体与靶标的同时结合时，这些反应性基团形成共价连接，导致双凸的形成，从而与蛋白质的结合口袋进行了多种相互作用。具体目的是：（1）设计和生产针对ATP结合位点的化合物的库，并携带其他官能团以进行现场点击化学；在体外筛选这些文库的ATP竞争力AKT抑制剂，这些抑制剂将用作锚分子。 （2）用与Akt结合的锚固分子进行原位点击化学反应并产生二价Akt配体。 （3）确定二价AKT抑制剂的效力和特异性，执行基于细胞的测定方法，以干扰Akt诱导的致癌转化。 （4）通过原位点击化学调查结构活性关系，并优化抑制剂，以提高效力，选择性和基于细胞