Abstract
Background: Recent developments in ITC instrumentation, namely MicroCal iTC200 and MicroCal Auto-iTC200 have led to an increase in the throughput and decrease in the protein consumption of the technique. In addition, there have been recent methodological Advancements 1 that have extended the affinity range that ITC can measure into the mM range. The combination of all these factors has made the technique ideal for fragment-based drug discovery (FBDD) campaigns. Method: This work outlines the role of MicroCal Auto-iTC200, in the fragment based drug discovery program of Sprint Bioscience, to identify and optimize potential drug candidates that will inhibit the activity of Vps34. This class phosphatidylinositol3-kinase is central to autophagy and has been shown to play an important role in resistance to cancer drugs2, 3. As such it has been identified as a target for therapeutic intervention. ITC is a generic assay without the need for assay development and as such the affinity of all 50 compounds was measured in less than three days after receiving the purified protein. Conclusion: This approach was fast and proved very successful for identifying fragments that co crystallized with the target protein. Of the14 compounds chosen, based on the ITC data, 12 formed crystals that could be used in the optimization process.