SELECTIVE INHIBITION OF EGF RECEPTOR TYROSINE KINASE

EGF 受体酪氨酸激酶的选择性抑制

• 批准号: 6362694
• 负责人: Thomas J. Burke
• 金额: $ 38.77万
• 依托单位: PANVERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362694
• 关键词: antineoplastics; bioassay; drug design /synthesis /production; enzyme inhibitors; enzyme substrate; epidermal growth factor; fluorescence polarization; growth factor receptors; immunoaffinity chromatography; protein purification; protein tyrosine kinase; receptor expression; technology /technique development; tissue /cell culture

Numerous studies have shown that the EGF receptor overexpression and mutation are associated with several intractable cancers, and that its intrinsic kinase activity is required for most of its biological effects. Recent efforts to develop anticancer agents targeting EGF receptor have focused on inhibition of the receptor tyrosine kinase activity. However, these efforts have been hampered by the lack of robust high throughput screening methods and insufficient understanding of the molecular basis of catalysis for the wild type and mutant forms of the receptor. To address these problems, PanVera's SBIR studies will develop a technology platform that will enable discovery of improved anticancer agents that selectively inhibit oncogenic EGF receptor variants. Phase I efforts will focus on developing sensitive, non-radioactive, homogenous high throughput assays for EGF receptor tyrosine kinase activity. In Phase II, these novel assays will be used to perform in vitro kinetic analysis of the function and differential inhibition of the WT and several mutant forms of the EGF receptor, which will be validated with cell-based studies. In Phase III, the new assays and data will be commercialized through sales and licensing to PanVera's extensive drug discovery customer base. PROPOSED COMMERCIAL APPLICATIONS: The Phase I SBIR studies will result in development of a proprietary, homogenous fluorescence polarization assay in a high throughput format to screen for EGF receptor kinase antagonists, which will be sold through PanVera's domestic and international distribution network, along with Phase II products such as cell-based and in vitro assays and related components for oncogenic EGF receptors. The validated approach for discovery of anti-cancer agents based on selective inhibition of these receptors will be commercialized through strategic alliances with pharmaceutical firms.

许多研究表明，EGF受体过表达和突变与几种难治性癌症有关，并且其内在激酶活性是其大部分生物学效应所必需的。最近开发靶向EGF受体的抗癌剂的努力集中在抑制受体酪氨酸激酶活性上。然而，这些努力受到缺乏强大的高通量筛选方法和对野生型和突变型受体催化的分子基础的理解不足的阻碍。为了解决这些问题，PanVera的SBIR研究将开发一个技术平台，该平台将能够发现选择性抑制致癌EGF受体变体的改良抗癌药物。第一阶段的工作将集中在开发敏感的，非放射性的，同质的高通量测定EGF受体酪氨酸激酶活性。在第二阶段，这些新的测定将用于进行体外动力学分析的功能和差异抑制的WT和几种突变形式的EGF受体，这将是验证与基于细胞的研究。在第三阶段，新的分析和数据将通过销售和许可PanVera广泛的药物发现客户群进行商业化。拟议的商业应用：第一阶段SBIR研究将导致开发一种专有的、同质的荧光偏振分析方法，以高通量的形式筛选EGF受体激酶拮抗剂，该方法将通过PanVera的国内和国际分销网络销售，沿着第二阶段产品，如基于细胞的和体外分析方法以及致癌EGF受体的相关成分。通过与制药公司的战略联盟，将通过选择性抑制这些受体的有效方法来发现抗癌剂。