Structure Based Discovery of AKT Inhibitors

基于结构的 AKT 抑制剂发现

• 批准号: 6465488
• 负责人: ROBERT I. GLAZER
• 金额: $ 15.52万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6465488
• 关键词: antineoplastics; apoptosis; binding sites; cell line; chemical information system; chemical structure function; dimer; drug discovery /isolation; enzyme inhibitors; isozymes; neoplasm /cancer; neoplasm /cancer pharmacology; protein kinase

DESCRIPTION (provided by applicant): AKT1 (protein kinase B) is the cellular homolog of the v-akt oncogene, and represents one of three isoforms of a multigene protein-serine/threonine kinase family. Gene amplification and/or overexpression of one or more Akt isoforms have been noted in cancers of the stomach, brain, breast, prostate, ovary and pancreas. High AKT activity is particularly evident in tumors with mutations or deletion of the tumor suppressor, PTEN, which functions primarily as a phosphoinositide 3-phosphatase. Expression of wild-type PTEN in human tumor cell lines or an AKT2 antisense cDNA in a human pancreatic carc/noma xenograft dramatically reduced cell and tumor growth, respectively, suggesting the utility of AKT as a therapeutic target. The broad objective of this application, therefore, is to develop isoform-specific inhibitors of AKT through the use of molecular modeling and virtual screening of compound libraries coupled with a unique screening assay based on homodimerization of the/soform-specific N-terminal donaain (AH domain) of AKT. Lead drugs identified in this screen will be assessed for their ability to inhibit tumor cell growth, induce apoptosis and block AKT activation via transphosphorylation. This application will address the hypothesis that interruption of AKT dimerization will inhibit its activity and downstream effector pathways leading to inhibition of tumor cell proliferation and activation of apoptosis. This hypothesis will be addressed by the following Specific Aims: 1) To refine our AKT1 model and to use it in construction of the homodimer resulting from interaction of the AH domains, 2) To identify structural regions in the AKT AH domain located at the interface of the AKT homodimer and to use virtual screening of compound libraries (NCI, ACD) to identify small molecules capable of interacting with these dimerization regions, and 3) To test those compounds showing the best scoring function for binding to the AH domain for their ability to inhibit AKT dimerization, and thus, activation of AKT in vitro. Based upon the latter results, structure-activity relationship (SAR) data will be generated by chemical modificationm of the lead molecules in order to improve compound activity. Modeling of active structures to the AKT1 AH domain binding pocket will be used in an iterative manner to guide compound synthesis as well as to suggest possible compound libraries to be created using combinatorial chemistry methods.

描述（由申请人提供）： AKT1（蛋白激酶 B）是 v-akt 癌基因的细胞同源物，并且 代表多基因蛋白丝氨酸/苏氨酸的三种亚型之一 激酶家族。一种或多种 Akt 的基因扩增和/或过表达 已在胃癌、脑癌、乳腺癌、前列腺癌、 卵巢和胰腺。高 AKT 活性在肿瘤中尤其明显 肿瘤抑制基因 PTEN 突变或缺失，其主要功能是 作为磷酸肌醇 3-磷酸酶。野生型PTEN在人体内的表达 人胰腺癌/坏瘤中的肿瘤细胞系或 AKT2 反义 cDNA 异种移植分别显着减少了细胞和肿瘤的生长，表明 AKT 作为治疗靶点的效用。本次活动的总体目标 因此，我们的申请是开发 AKT 异构体特异性抑制剂 通过使用分子建模和化合物的虚拟筛选 文库结合基于同源二聚化的独特筛选测定 AKT 的/soform 特异性 N 末端氨基酸（AH 结构域）。铅药物 将评估此筛选中确定的抑制肿瘤的能力 细胞生长、诱导细胞凋亡并通过阻断 AKT 激活 转磷酸化。该应用程序将解决以下假设： AKT二聚化的中断将抑制其活性和下游 效应途径导致抑制肿瘤细胞增殖和 细胞凋亡的激活。这一假设将通过以下内容得到解决 具体目标： 1) 完善我们的 AKT1 模型并将其用于构建 AH 结构域相互作用产生的同二聚体，2) 鉴定 AKT AH 结构域中的结构区域位于 AKT 界面 同二聚体并使用化合物库（NCI、ACD）的虚拟筛选 识别能够与这些二聚化相互作用的小分子 区域，以及 3) 测试那些表现出最佳评分功能的化合物 与 AH 结构域结合，抑制 AKT 二聚化，以及 因此，AKT 在体外被激活。根据后面的结果， 结构-活性关系（SAR）数据将由化学生成 修饰先导分子以提高化合物活性。 AKT1 AH 结构域结合口袋的活性结构建模将是 以迭代方式用于指导化合物合成并提出建议 使用组合化学创建可能的化合物库 方法。