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

描述（由申请人提供）：由于癌症是美国主要的死亡原因之一，一些亚型基本上无法治疗，因此扩大可用的药物靶点将为开发更有效的抗癌药物提供重要的新选择。该项目的主要目标是将独特的药物发现策略应用于癌症药物开发。这将通过应用这种方法来发现和表征破坏与抗癌治疗相关的相互作用的新型药物样小分子治疗剂来实现。开发基于蛋白质-蛋白质相互作用抑制剂的药物的改进策略将是有益的，以克服目前大多数可药用靶点对涉及配体-受体和酶-底物相互作用的靶点的限制。我们将把我们的努力集中在细胞周期蛋白依赖性激酶底物招募网站作为一个验证的抗肿瘤药物的目标。通过该位点，存在开发对细胞周期CDK特异性的有效和选择性抑制剂的机会。此类具有适当药物样特征的化合物在机理上可能与ATP竞争性CDK抑制剂不同，选择性靶向肿瘤细胞，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-蛋白质复合物的结合，并应用这种方法来发现新的药物样小分子治疗剂，破坏与抗癌治疗相关的这种相互作用。我们将重点关注细胞周期蛋白依赖性激酶底物募集位点，通过该位点有机会开发出特异于细胞周期CDK的有效和选择性抑制剂。具有适当药物样特征的此类化合物在机理上将不同于ATP竞争性CDK抑制剂，选择性靶向肿瘤细胞并解决目前正在开发的药剂的问题。

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.