Chemistry Technology Projects

The discovery of mechanistically defined bioactive small molecules continues at a breakneck pace. Whether they are approved drugs or preclinical probe compounds, understanding how different biological systems respond to these tools is a critical step in broadening our basic understanding of systems biology and the translational potential of mechanistic perturbation.

Our team utilizes a variety of chemistry technologies to develop new, mechanistically defined small molecule tools. We also survey the scientific literature to find and collect new and exciting small molecules to populate our chemogenomics screening libraries. Our primary library is called the Mechanistic Interrogation PlatE (or MIPE). We are currently on the sixth generation of this library which is used in a myriad of phenotypic screening studies across NCATS teams. For key target classes (like kinase inhibitors), we also conduct profiling efforts to gauge selectivity and the possibility for off-target positioning into new indications or as the starting point for new polypharmacology-informed optimization efforts.  

Highlights from our small molecule discovery work include the first reported small molecule activators of the M2 isoform of pyruvate kinase and a recently disclosed dual FLT3/IRAK1/4 inhibitor. While we don’t set out to discover new drugs, several agents discovered in our lab have moved into human clinical evaluations, including Zalunfiban and 2R,6R-hydroxynorketamine.

Discovery of Small Molecule PKM2 Activators

Pyruvate kinase catalyzes the transformation of phosphoenolpyruvate and ADP to pyruvate and ATP and is the penultimate step in the glycolytic process. The M2 isoform is catalytically inactive and rate limiting. Certain cells, including most cancer cells, choose to express this isoform to support the metabolic program of rapidly proliferating cells. Collaborating with the Cantley and Vander Heiden labs, our team  discovered and optimized the first small molecule activators of PKM2. These agents helped confirm the role of PKM2 in cancer cell metabolism and expanded our understanding of the role of this enzyme in several other phenotypes, including inflammation (Anastasiou, et al. Science 2011, 334, 1278-1283 and Palsson-McDermott, Cell Metabolism, 2015, 21, 65-80).