Targeting Akt with substrate mimetic antagonists

用底物模拟拮抗剂靶向 Akt

基本信息

批准号：
8549176
负责人：
Juan R Del Valle
金额：
$ 17.22万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549176
关键词：
Animals Apoptosis Apoptotic Automobile Driving Binding Binding Sites Biological Biological Assay Biology Calorimetry Cell Cycle Progression Cell membrane Cells Chemicals Cleaved cell Clinical Defect Development Dose Evaluation Exhibits FDA approved Family Genes Genetic Transcription Goals Growth Human In Vitro Inhibitory Concentration 50 Laboratories Lead Length Libraries Ligands Link Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Metabolism Mitotic Cell Cycle Mutation N-terminal Nature Nodal Oncogenic PH Domain Pancreatic Adenocarcinoma Pathway interactions Peptides Phosphatidylinositols Phosphorylation Phosphotransferases Play Principal Investigator Process Property Protein Binding Domain Proteins Relative (related person)Reporting Research Project Grants Resistance Roentgen Rays Role Signal Pathway Signal Transduction Signaling Protein Site Structure Testing Therapeutic TimeLine Titrations Validation Work X-Ray Crystallography analog anti-cancer therapeutic base cancer therapy design hormone refractory prostate cancer in vitro activity in vivo inhibitor/antagonist malignant breast neoplasm malignant stomach neoplasm mimetics neoplastic cell novel peptide structure phosphatidylinositol 3,4,5-triphosphate platelet protein P47 process optimization programs protein protein interaction research study treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): The increased proliferation rate and progression of various cancers can be directly linked to defects in apoptotic signaling cascades. Akt is a central protein in the PI3K pathway that confers resistance to apoptosis through inactivation of intracellular substrates. Hyperactivation of Akt is essential in the initiation and maintenance of over 50% of all human tumors. The most common include breast, ovarian, pancreatic, and gastric cancers, as well as the particularly aggressive hormone-refractory prostate cancers. Inhibition of the kinase activity of Akt is a clinically validated strategy for the treatment of thse malignancies. However, most efforts directed toward this end focus on agents that displace endogenous ATP from the Akt binding pocket-a strategy that often yields promiscuous lead compounds that inhibit other homologous kinases. In contrast, our laboratory is engaged in the development of Akt inhibitors that specifically target the protein substrate-binding cleft adjacent to the ATP site. The rationale behind this approach is the notion that the protein-protein interaction (PPI) region of Akt harbors a far more discerning topology relative to other binding sites. Recent X- ray co-crystal structures of Akt bound to truncated sections of its endogenous substrate GSK3b have informed the design of various peptide lead structures. Although targeting the PPI domain of Akt is presumably more difficult due to the extensive interaction region, a number of compelling factors have prompted us to pursue a PPI-targeting strategy, including (1) the discovery, in our lab, of a potent substrate mimetic lead inhibitor with reduced peptide character, (2) a structural rationale for refinements based on X-ray crystallography, (3) extensive clinical validation for targeting Akt, and (4) the lack of an FDA-approved Akt inhibitor for the treatment of cancer. Here, we propose the structure-based design and synthesis of a focused library of analogs based on our lead inhibitor, and their biological evaluation in vitro an in whole cell assays. The objective of this project is to provide the first non-peptide substrate mimetic inhibitors capable of selectively targeting Akt-dependant tumor cells. Our longer-term goals are to use a PPI approach to develop clinical candidates with more favorable therapeutic profiles and to apply this strategy to the inhibition of other oncogenic kinases.

描述（由申请人提供）：各种癌症的增殖率和进展增加可以直接与凋亡信号级联反应的缺陷联系起来。 AKT是中心 PI3K途径中的蛋白质通过灭活细胞内底物赋予对凋亡的抗性。 AKT的过度激活对于启动和维持所有人类肿瘤的50％至关重要。最常见的包括乳房，卵巢癌，胰腺和胃癌，以及特别侵略性的激素 - 饮食前列腺癌。抑制AKT的激酶活性是治疗恶性肿瘤的临床验证策略。但是，大多数针对这一目的的努力都集中在使内源性ATP从Akt结合袋中取代的药物 - 通常会产生抑制其他同源激酶的混杂铅化合物。相比之下，我们的实验室参与了AKT抑制剂的开发，这些抑制剂专门针对蛋白质底物结合裂口到ATP站点。这种方法背后的理由是，Akt的蛋白质 - 蛋白质相互作用（PPI）相对于其他结合位点具有更具敏感性的拓扑结构。 Akt的最新X射线共结构结构与其内源性基板GSK3B的截断部分结合在一起，已告知各种肽铅结构的设计。尽管由于广泛的相互作用区域，靶向AKT的PPI域可能更加困难，但许多引人注目的因素促使我们采取PPI靶向策略，包括（1）在我们的实验室中发现，在我们的实验室中发现了有效的底物模拟铅抑制剂具有较低的肽限制的固定剂，（2）X-READERIDATH，（2）X-READERIDENT（2）X-READERIDATION（2）REDAINS CRYTISTICT（2）针对AKT，以及（4）缺乏FDA批准的AKT抑制剂来治疗癌症。在这里，我们提出了基于结构的设计和基于铅抑制剂的聚焦类似物库的合成，并在整个细胞分析中在体外AN中进行了生物学评估。该项目的目的是提供能够选择性靶向Akt依赖性肿瘤细胞的第一个非肽底物抑制剂。我们的长期目标是使用PPI方法来开发具有更有利治疗特征的临床候选者，并将这种策略应用于抑制其他致癌激酶。