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.
Proteins and other biological molecules adopt different shapes or ‘conformations’ that determine the various functions they carry out. Biodesy has developed a highly sensitive method for detecting these changes in real time. The method involves detecting the position in space of a small tag attached to the biological molecule, somewhat analogous to the sensors used by golfers to analyze their swing. We can vary the position of the tags to watch how different parts of the biological molecule change conformation. Our Phase I project demonstrated that we can detect conformation changes of an important protein called Abl kinase, by attaching tags into the protein at various positions. Drugs or other small molecules can bind to this protein and cause different changes in conformation, and we successfully detected these in the project. Abl kinase is important because it is important because it is the target of a remarkable drug called Gleevec used to treat a form of leukemia. In patients with a mutation in the protein, Abl kinase is always on (‘constitutively active’). Gleevec inactives the mutated protein and keeps the cancer at bay. That Gleevec changes the conformation of Abl kinase was determined by a method called X-ray crystallography, which involves taking a snapshot of a protein's atoms using x-rays. This method is popular and very powerful, but it is slow and difficult to run. It also requires freezing the protein into a crystal, rather than keeping it in its native environment, which can lead to questions about its accuracy. Biodesy’s method by contrast allows the protein to exist in more or less its native environment – in water – and is simple to run. In part with funding from the National Science Foundation, we plan to develop our instruments for the entire scientific community - in academia and in companies - to speed up the search for other Gleevecs and for basic research applications directed at understanding how proteins work or are broken when mutated.
