Development of cFLIP-calmodulin interaction inhibitors for lung cancer therapy
Maria Pellegrini, Ph.D.
Research Assistant Professor of Chemistry Dartmouth College
Dale F. Mierke, Ph.D.
Professor of Chemistry Dartmouth College
The focus of our research is the characterization of protein-protein interactions and their modulation through design and synthesis of peptide and small molecular weight inhibitors. Our efforts leverage the strength of structural biology coupled with biophysical and biochemical techniques. The Pilot Project funded by the COBRE Lung Biology Center Program aims at developing molecular inhibitors cFLIP, an oncogenic protein upregulated in numerous cancers including NSCLC, where it is hypothesized to be the main driver in the loss of apoptosis. This is supported by the observation that siRNA-based downregulation of cFLIP leads to a re-sensitization of the cells to TRAIL induced apoptosis. Additionally, it has been described that CaM also has an anti-apoptotic effect, and promotes proliferation, whereas CaM antagonists cause apoptosis.
We have collected evidence that cFLIP interacts directly with CaM through its death-effector domain 1 (DED1). In our current working model CaM acts as a scaffold that recruits cFLIP into the DISC, and therefore it is the primary enabler of cFLIP's apoptosis blocking activity. Based on this insight, we are developing macrocyclic inhibitors that target the cFLIP-DED1 and thereby the formation of the cFLIP/CaM association. The ultimate goal of the project is to inhibit the recruitment of cFLIP to the DISC, and thereby restore the extrinsic apoptotic pathway induced by chemotherapy.