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能与细胞凋亡信号级联的缺陷直接相关。 Akt 是一个中心 PI3K 通路中的蛋白质，通过细胞内底物的失活来抵抗细胞凋亡。 Akt 的过度激活对于超过 50% 的人类肿瘤的发生和维持至关重要。最常见的癌症包括乳腺癌、卵巢癌、胰腺癌和胃癌，以及特别具有侵袭性的激素难治性前列腺癌。抑制 Akt 激酶活性是治疗这些恶性肿瘤的经过临床验证的策略。然而，大多数针对此目的的努力都集中在从 Akt 结合袋中置换内源 ATP 的药物上，这种策略通常会产生混杂的先导化合物，从而抑制其他同源激酶。相比之下，我们的实验室致力于开发专门针对邻近蛋白质底物结合裂隙的 Akt 抑制剂。到 ATP 站点。这种方法背后的基本原理是 Akt 的蛋白质-蛋白质相互作用 (PPI) 区域相对于其他结合位点具有更具识别性的拓扑结构。最近的 Akt 与其内源性底物 GSK3b 的截断部分结合的 X 射线共晶结构为各种肽先导结构的设计提供了信息。尽管由于广泛的相互作用区域，靶向 Akt 的 PPI 结构域可能更加困难，但许多令人信服的因素促使我们追求 PPI 靶向策略，包括 (1) 在我们的实验室中发现了一种有效的底物模拟物具有减少肽特征的先导抑制剂，(2) 基于 X 射线晶体学的改进的结构原理，(3) 针对 Akt 的广泛临床验证，以及 (4) 缺乏 FDA 批准的 Akt 抑制剂用于治疗癌症。在这里，我们提出基于我们的先导抑制剂的重点类似物库的基于结构的设计和合成，以及它们的体外和全细胞测定的生物学评估。该项目的目标是提供第一个能够选择性靶向 Akt 依赖性肿瘤细胞的非肽底物模拟抑制剂。我们的长期目标是使用 PPI 方法开发具有更有利治疗特性的临床候选药物，并将该策略应用于抑制其他致癌激酶。