SBIR Phase I: Development of a Conformational Screen for Rapidly Identifying Kinase Inhibitor Type Using SHG

SBIR 第一阶段：开发利用 SHG 快速识别激酶抑制剂类型的构象筛选

• 批准号: 1142241
• 负责人: Joshua Salafsky
• 金额: $ 15万
• 依托单位: Biodesy, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1142241&HistoricalAwards=false
• 关键词: SBIR; Phase; Development; Conformational; Screen

This Small Business Innovation Research (SBIR) Phase I project builds on the rapid FDA approval success of recent cancer therapeutics that act on a specific conformation state of their target protein. Biodesy has developed a new optical technique, Second Harmonic Generation that measures protein conformation in real time and addresses the challenge of rapidly identifying and discriminating ligands that bind to or induce different protein conformations. They are applying this technique to understanding the critical protein conformations that distinguish the different classes of inhibitors against protein kinases. Biodesy plan to use site-specific mutations of cysteines within Abl kinase to identify and measure conformation changes at discrete areas within the protein and study how these are modified in the presence and absence of different classes of inhibitors.The broader/commercial implications of this research are to provide a comprehensive, high throughput platform that will enable the rapid identification of novel therapeutics. The FDA recently provided accelerated approval to a structure-specific inhibitor of BRaf, Vemurafenib, which functions by holding its targeted protein in an inactive conformation state. Gleevec (revenue in excess of $4B), functions in a similar fashion. Interest in techniques that can identify this mechanism of action has grown markedly. Biodesy?s platform has the potential to greatly accelerate identification and development of similar therapeutics. There are more than 500 kinases in the kinome so the commercial potential of the approach is significant. Furthermore, its broader impact is to provide a general method for identifying conformation-specific drugs across all target classes.

这个小型企业创新研究（SBIR）第一阶段项目建立在最近的癌症治疗药物的快速FDA批准成功的基础上，这些药物作用于其靶蛋白的特定构象状态。生物测定学开发了一种新的光学技术，二次谐波产生，测量蛋白质构象在真实的时间和解决的挑战，快速识别和区分配体结合或诱导不同的蛋白质构象。他们正在应用这项技术来了解关键的蛋白质构象，以区分不同类别的蛋白激酶抑制剂。Biodesy计划利用Abl激酶内半胱氨酸的位点特异性突变来识别和测量蛋白质内离散区域的构象变化，并研究在存在和不存在不同类型抑制剂的情况下这些区域如何被修饰。这项研究的更广泛/商业意义是提供一个全面的高通量平台，能够快速识别新型疗法。FDA最近加速批准了BRaf的结构特异性抑制剂Vemurafenib，其功能是将其靶蛋白保持在非活性构象状态。格列卫（收入超过40亿美元）以类似的方式发挥作用。对能够识别这种作用机制的技术的兴趣显著增长。生物测定学？该平台有可能大大加快类似疗法的识别和开发。在激酶组中有超过500种激酶，因此该方法的商业潜力是显著的。此外，其更广泛的影响是提供一种通用方法，用于识别所有目标类别的构象特异性药物。