Non-ATP competitive inhibitors of cyclin dependent kinases as cancer therapeutics

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。通过这个网站，机会 存在的目的是开发针对细胞周期CDKs的有效和选择性的抑制剂。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。

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.