SELECTIVE INHIBITION OF EGF RECEPTOR TYROSINE KINASE

大量研究表明，EGF受体的过度表达和突变与几种难治性癌症有关，其内在的激酶活性是其大部分生物学效应所必需的。最近针对EGF受体的抗癌药物的开发主要集中在抑制受体酪氨酸激酶的活性上。然而，由于缺乏可靠的高通量筛选方法，以及对野生型和突变型受体催化的分子基础了解不足，这些努力一直受到阻碍。为了解决这些问题，PanVera的SBIR研究将开发一个技术平台，使发现选择性抑制致癌EGF受体变体的改进抗癌剂成为可能。第一阶段的工作将集中于开发敏感的、非放射性的、均一的高通量EGF受体酪氨酸激酶活性检测方法。在第二阶段，这些新的分析方法将用于体外动力学分析WT和几种突变形式的EGF受体的功能和不同的抑制作用，这将通过基于细胞的研究进行验证。在第三阶段，新的分析和数据将通过向PanVera广泛的药物发现客户群进行销售和许可而商业化。拟议的商业应用：第一阶段SBIR研究将以高通量形式开发一种专有的、均一的荧光偏振分析，以筛选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与第二阶段产品一起销售，如基于细胞的和体外分析以及致癌EGF受体的相关组件。经过验证的基于选择性抑制这些受体的抗癌药物发现方法将通过与制药公司的战略联盟进行商业化。

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.