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

这项小型企业创新研究（SBIR） I期项目建立在FDA对最近癌症治疗药物的快速批准成功的基础上，这些药物作用于其靶蛋白的特定构象状态。Biodesy开发了一种新的光学技术，二次谐波生成，实时测量蛋白质构象，解决了快速识别和区分结合或诱导不同蛋白质构象的配体的挑战。他们正在应用这项技术来了解区分不同种类的蛋白激酶抑制剂的关键蛋白质构象。Biodesy计划利用Abl激酶中半胱氨酸的位点特异性突变来识别和测量蛋白质中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构象是如何被修饰的。这项研究的更广泛/商业意义是提供一个全面的、高通量的平台，使新的治疗方法能够快速识别。FDA最近加速批准了一种BRaf结构特异性抑制剂Vemurafenib，其作用是将其靶蛋白保持在非活性构象状态。格列卫（营收超过40亿美元）的运作方式与此类似。对能够识别这种作用机制的技术的兴趣已显著增长。Biodesy吗?S平台有潜力极大地加速类似疗法的识别和开发。在kinome中有超过500种激酶，因此该方法的商业潜力是巨大的。此外，其更广泛的影响是提供了一种通用的方法来识别所有目标类别的构象特异性药物。

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.