Author's Department/Program
Biology and Biomedical Sciences: Computational and Systems Biology
Language
English (en)
Date of Award
January 2009
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Chair and Committee
Garland Marshall
Abstract
The epidermal growth factor receptor: EGFR) is a membrane receptor tyrosine kinase whose over-activation has been implicated to cause many human cancers. Novel strategies to inhibit the activation of EGF receptors other than the conventional antibody-based and tyrosine kinase inhibitors are virtually non-existent but could provide benefits both in the laboratory and clinical settings. In an effort to expand the current approaches, this thesis focused on targeting the homodimerization of the EGF receptors themselves and the heterodimerization of EGF receptors with the related ErbB2 receptor. Three sub-projects were completed in the process. The first project explored the feasibility of inhibiting the EGF receptor by targeting receptor dimerization with small molecules. Two lead compounds were initially predicted by virtual screening the NCI compound library, and were biochemically characterized. The benefit gained from the application of virtual screening in this project initiated another project to enhance the accessibility of virtual screening within the non-computational community. The OpenScreening project utilizes distributed computing resources and provides open-access screening server at: http://omg.phy.umassd.edu/xvhts. A final project identified the structural mechanism that may explain the observed preference of EGFR-ErbB2 heterodimerization over EGFR homodimerization. Key residues were computationally predicted and biochemically tested to reveal critical dimerization interface.
Recommended Citation
Yang, Rob, "Targeting The Dimerization Of ERBB Receptor Tyrosine Kinases" (2009). All Theses and Dissertations (ETDs). 391.
https://openscholarship.wustl.edu/etd/391
Comments
Permanent URL: http://dx.doi.org/10.7936/K7VQ30NW