|Name||Mrs. Elham Yaaghubi|
|Organization or Institution||University of Florida|
A New Class of Compounds Active Against HER2+ and EGFR+ Cancer Cells: Mechanism of Action Studies and Optimization.
Elham Yaaghubi1, Amanda F. Ghilardi1, Renan B. Ferreira1, Mengxiong Wang2, Mary E. Law2, Bradley J. Davis2, Coy D. Heldermon3, Brian K. Law2, and Ronald K. Castellano1
1 Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL 32611-7200, USA
In contrast to conventional therapies that kill all rapidly dividing cells and therefore can cause serious side effects, targeted therapies act against specific proteins responsible for cancer signaling. The overexpression of EGFR, HER2, and HER3 initiates strong and constant signaling cascades that accelerates cell growth beyond its normal limits and hence leads to a wide variety of types of tumors, including breast and lung cancers. This fact motivated the development of inhibitors that target these receptors. However, the activity of these agents is affected by therapeutic resistance, whose important source is the functional redundancy among EGFR, HER2, and HER3. Therefore therapies that inactivate EGFR/HER2/HER3 in parallel can be an effective treatment. We have previously shown that a novel class of compounds, termed Disulfide-bond Disrupting Agents (DDAs), downregulate EGFR/HER2/HER3 in parallel, suppress AKT phosphorylation, induce ER stress, and effectively kill EGFR+ and HER2+ breast cancer both in vitro and in vivo with no observed toxicity. In this work, first we are continuing our studies on DDA mechanism of action by designing and synthesizing molecular probes to get evidence for DDA direct targets. Second, we aim to optimize the DDA potency first by increasing the number of pharmacophore repeats per drug molecule, and second by exploring new derivatives and studying the pharmacophore tolerance upon functionalization.