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Cell cycle specific CDK inhibitors as potential anti-tumor therapeutics through R

细胞周期特异性 CDK 抑制剂作为潜在的 R 抗肿瘤疗法

基本信息

批准号：
7898735
负责人：
Campbell McInnes
金额：
$ 28.04万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898735
关键词：
Address Antineoplastic Agents Apoptosis Area Binding C-terminal CDK2 gene Cardiovascular Diseases Cause of Death Cell Cycle Cell Cycle Inhibition Cell Proliferation Cells Characteristics Chemicals Complex Cyclin A Cyclin-Dependent Kinases Cyclins Data Development Docking Drug Delivery Systems Drug Kinetics E2F1 gene Epitopes G1 Phase Generations Goals Hybrids In Vitro Induction of Apoptosis Investigation Lead Libraries Ligands Link Malignant Neoplasms Mediating Methodology Methods Modeling Modification Molecular Weight Mus Organic Chemistry Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phenotype Phosphorylation Phosphorylation Inhibition Plasma Proteins Property Protein Binding Protein Kinase Inhibitors Proteins Reporter Roentgen Rays Site Solubility Staging Structure Substrate Interaction Techniques Testing Therapeutic United States Work Xenograft procedure antitumor agent antitumor drug base cancer cell cancer therapy cell growth cell killing cytotoxicity design drug development drug discovery enzyme substrate experience improved in vitro Assay in vivo inhibitor/antagonist mouse model neoplastic cell novel oncology pre-clinical preclinical study programs protein complex protein kinase inhibitor protein protein interaction public health relevance receptor scaffold small molecule tumor virtual

项目摘要

DESCRIPTION (provided by applicant): As cancer is one of the leading causes of death in the United States with some sub-types remaining essentially untreatable, expansion of available drug targets will provide significant new options for the development of more effective antineoplastic agents. The major goal of this project is to apply a unique drug discovery strategy to cancer drug development. This will be accomplished through application of this methodology to the discovery and characterization of new drug-like small molecule therapeutics disrupting interactions relevant to anti-cancer therapy. Improved strategies for developing pharmaceuticals based on inhibitors of protein-protein interactions would be beneficial in order to overcome the limitations of the majority of currently druggable targets to those involving ligand-receptor and enzyme-substrate interactions. We will focus our efforts on the Cyclin Dependent Kinase substrate recruitment site as a validated antitumor drug target. Through this site, the opportunity exists to develop potent and selective inhibitors that are specific to the cell cycle CDKs. Such compounds possessing appropriate drug-like characteristics will potentially be different mechanistically from ATP competitive CDK inhibitors, targeting tumor cells selectively and thereby addressing issues with agents currently being developed. PUBLIC HEALTH RELEVANCE:The major goal of this project is extend and further validate a unique drug discovery strategy for blocking the association of protein-protein complexes and to apply this methodology to discover new drug-like small molecule therapeutics disrupting such interactions relevant to anti-cancer therapy. We will focus on the Cyclin Dependent Kinase substrate recruitment site, through which the opportunity exists to develop potent and selective inhibitors that are specific to the cell cycle CDKs. Such compounds possessing appropriate drug-like characteristics will be different mechanistically from ATP competitive CDK inhibitors, targeting tumor cells selectively and addressing issues with agents currently being developed.

描述(申请人提供)：由于癌症是美国的主要死亡原因之一，一些亚型仍然基本上无法治疗，现有药物靶点的扩大将为开发更有效的抗肿瘤药物提供重要的新选择。该项目的主要目标是将一种独特的药物发现策略应用于癌症药物开发。这将通过将这一方法学应用于发现和表征破坏与抗癌治疗相关的相互作用的新药类小分子疗法来实现。改进基于蛋白质-蛋白质相互作用抑制剂的药物开发策略将是有益的，以便克服目前大多数可药物靶标对涉及配体-受体和酶-底物相互作用的靶标的限制。我们将把我们的努力集中在Cyclin依赖的激酶底物招募部位，作为一个有效的抗肿瘤药物靶点。通过这个站点，存在着开发针对细胞周期CDKs的有效和选择性抑制物的机会。这些具有适当类药物特征的化合物可能在机制上不同于ATP竞争性CDK抑制剂，选择性地靶向肿瘤细胞，从而解决目前正在开发的药物的问题。公共卫生相关性：该项目的主要目标是扩展和进一步验证一种独特的药物发现策略，用于阻断蛋白质-蛋白质复合体的关联，并应用这种方法来发现新的药物类小分子疗法，破坏与抗癌治疗相关的这种相互作用。我们将专注于细胞周期蛋白依赖性的激酶底物招募位点，通过该位点有机会开发出针对细胞周期CDKs的有效和选择性的抑制物。这些具有适当类药物特征的化合物在机制上将不同于ATP竞争性CDK抑制剂，它们选择性地靶向肿瘤细胞，并解决目前正在开发的药物的问题。