Synthesis and Testing of Small Molecule Inhibitors of Arp2/3 Complex

The first aim of this research project was to design several new inhibitor candidates through a collaboration with a computational chemist, Dr. Zoe Cournia at the Bioacademy of Athens. We corresponded with Dr. Cournia during the grant period and submitted to her research group a number of new designs we generated for our inhibitor molecules. Work is ongoing on her end to use computational modeling software to predict the efficacy of our designed molecules, and feedback from her work will guide our future efforts in synthesis. The second aim of this research project was to synthesize several new inhibitor candidates that had already been designed and identified by Dr. Cournia as having high potential as potent Arp2/3 complex inhibitors. The students who worked on this project spent the majority of their 400 hours in my research lab carrying out this part of the project. Their efforts over the summer resulted in the synthesis and purification of 16 new molecules, 13 of which are novel, unpublished chemical structures. The students purified the samples of the molecules and collected analytical data about each one to publication-ready quality. Furthermore, the students identified several optimizations to their reactions that will help future synthesis efforts. The final aim of this research project was to study the activity of new inhibitor candidates in actual trials with our target protein, Arp2/3 complex. We traveled to the lab of our collaborator, Dr. Brad Nolen at the University of Oregon, twice during the award period and collected data on a number of inhibitor candidates. This data collection is limited to times when Dr. Nolen’s lab purifies the proteins needed for our studies, so the data collection is ongoing