Trainee Spotlight: Krisna Duong-Ly, PhD
I first became interested in science in high school after taking several laboratory-based science courses that were taught by very enthusiastic teachers. After high school, I decided to study biochemistry at Swarthmore College and pursue a research project with Dr. Kathleen Howard. My undergraduate thesis focused on understanding how the conformational plasticity of an influenza A membrane protein responds to alterations in the lipid bilayer environment. Through this experience, I developed a deep interest in structural biology; I pursued this interest in graduate school at Johns Hopkins University School of Medicine in the laboratory of Dr. L. Mario Amzel. There, I studied the mechanism of PI3K activation and used both kinetics and structural methods, like X-ray crystallography and small-angle X-ray scattering, to identify and characterize two bacterial proteins belonging to a novel hydrolase family whose members act on substrates that contain nucleoside diphosphates.
Intrigued by my work on kinases, I sought postdoctoral opportunities in which to further my study of these important enzymes. I ultimately chose to pursue this interest in Dr. Jeffrey Peterson’s laboratory at Fox Chase Cancer Center where my work centers on identifying and characterizing novel kinase inhibitors of disease-associated mutant kinases and understanding the downstream signaling of kinases commonly activated in human cancers. My future career goals are to learn more about kinase-regulated processes and to develop novel therapeutics against kinase-driven diseases.
Kinases are key regulators of several biological processes, including cell proliferation, growth, motility, metabolism and apoptosis. These enzymes are important drug targets in several diseases, most notably in cancers where aberrant kinase activity can contribute to unregulated cell growth and tumor progression. Over 30 kinase inhibitors have been FDA-approved for various indications; however, many of these inhibit multiple kinases in addition to the target of interest. To evaluate the target spectrum of both commonly used clinical and research tool compounds, our lab, in collaboration with Reaction Biology Corporation, carried out a large-scale screen of 180 compounds against a panel of 300 recombinant human wild-type kinases. This screen revealed a number of unexpected compound/kinase interactions.
We have now expanded this study to include an additional 76 disease-associated mutant kinases. We recapitulated known inhibitor sensitivity and resistance data, but also uncovered promising novel lead compounds that target several mutant kinases as well as some opportunities for repurposing existing clinical compounds against novel indications. Furthermore, we demonstrate how this screening strategy can be used to guide subsequent optimization of lead compounds.
Duong-Ly KC, Devarajan K, Liang S, Horiuchi KY, Wang Y, Ma H, and Peterson JR. Kinase inhibitor profiling reveals unexpected opportunities to inhibit disease-associated mutant kinases. Cell Reports 2016 14(4):772-781.