My doctoral research experience has focused on using chemical tools to correct perturbed biological systems, primarily cancer. A recently develop tool in the Crews? lab, proteolysis targeting chimera (PROTACs), allows for the degradation of a protein of interest without any genetic manipulation. Thus far, I have focused on establishing PROTACs as a valuable tool. I have shown that these compounds behave according to our proposed mechanism, that they specifically and potently degrade the protein of interest, and that PROTACs can degrade their targets in animal models. For my F99 phase, I will focus on developing selective ligands that can be used in a PROTAC to degrade the pseudo-kinase KSR. This protein is not mutated or activated in cancer, but upregulates the Ras-MAPK pathway involved in many different cancers. By combining high-throughput screening with medicinal chemistry, I will first develop the selective ligand from a library of known kinase inhibitors. Once a ligand is developed, a PROTAC will be synthesized based on that ligand and assessed for KSR-degradation in cells. I will then use this tool to further clarify the scaffolding roles of KSR in the Ras-MAPK pathway and other cellular signaling pathways by using high-content peptide arrays. This project is an example of combining chemical biology tools with ?systems-level? insights in cancer. In my K00 phase, I hope to continue this line of thinking by being trained in high-content profiling techniques used to study the complex biochemical milieu that is often altered and mis-regulated in cancer and identify new targets. By combining integrative ?-omics? techniques with chemical biology, I will work to develop novel chemical tools for novel targets.
The proposed research focuses on a recently developed small-molecule tool, PROTACs, which induce the ubiquitination and degradation of a rationally targeted protein. By performing high-throughput screening and biophysical characterization, I will identify a selective ligand for KSR which can then be derivatized into a PROTAC that selectively degrades the protein. PROTACs against KSR will represent a novel step toward therapeutic treatment of traditionally ?undruggable? targets.
