Structure Based Discovery of AKT Inhibitors

基于结构的 AKT 抑制剂发现

• 批准号: 6623419
• 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/6623419
• 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，和 代表多基因蛋白丝氨酸/苏氨酸的三种同工型之一 激酶家族。一个或多个AKT的基因扩增和/或过表达 在胃，大脑，乳房，前列腺的癌症中已经注意到同工型， 卵巢和胰腺。在患有 肿瘤抑制剂PTEN的突变或缺失，主要起作用 作为磷酸肌醇3-磷酸酶。人类野生型PTEN的表达 肿瘤细胞系或人胰腺中的AKT2反义cDNA 异种移植物分别大大减少了细胞和肿瘤生长，表明 AKT作为治疗目标的实用性。这个广泛的目标 因此，应用是开发Akt的同工型特异性抑制剂 通过使用分子建模和化合物的虚拟筛选 库以及基于同构化的独特筛选测定法 Akt的/soform特异性n末端Donaain（AH域）。铅毒品 在此屏幕中确定的将评估其抑制肿瘤的能力 细胞生长，通过 经磷酸化。该申请将解决以下假设 Akt二聚化的中断将抑制其活性和下游 效应子途径导致抑制肿瘤细胞增殖和 凋亡的激活。该假设将通过以下来解决 具体目的：1）完善我们的AKT1模型并将其用于构建 由AH域相互作用产生的同型二聚体，2）识别 Akt AH域的结构区域位于Akt的界面 同二聚体并使用复合库（NCI，ACD）的虚拟筛选 识别能够与这些二聚体相互作用的小分子 区域和3）测试这些化合物，显示出最佳的评分功能 与AH结构域结合，以抑制Akt二聚化的能力，并且 因此，在体外激活Akt。基于后者的结果 结构活性关系（SAR）数据将通过化学生成 铅分子的修饰以改善复合活性。 对AKT1 AH结构域绑定袋进行主动结构的建模将是 以迭代方式用于指导化合物合成并暗示 可能使用组合化学创建的可能的复合库 方法。