Small Molecule Inhibitors of EGFR Ectodomain for Breast Cancer Therapy
Abstract
The goal of this proposal was to develop low molecular weight inhibitors of EGFR that disable receptor functioning by preventing critical activating transitions of the extracellular domain. A compound, EL1-FD1, has been created and found able to reverse the malignant properties of EGFR transformed cells in vitro and in vivo. EL1-FD1 was designed to limit the mobility of the EGFR ectodomain, in particular subdomains I and II. For Task 3a, we have optimized therapeutic administration of EL1-FD1 in animal tumor bearing models. For Task 3b, we have analyzed the effects of the compound in vitro in anchorage dependent and independent assays. None of the analogs we identified in Task 4 possessed greater activity than EL1-FD1. For Task 5 we have studied features of how the constrained EGFR binds ligand. The ability of the compound that constrains EGFR mobility to bind EGF was found to be dramatically reduced. We have not yet succeeded in co-crystallization as described in Task 6 and still are pursuing different conditions for formation of crystal structures of the complex.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2010
- Accession Number
- ADA538235
Entities
People
- Mark I. Greene
Organizations
- University of Pennsylvania