Small Molecule Inhibitors of EGFR Ectodomain for Breast Cancer Therapy

摘要

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. The lead compound, EL1-FD1, has been designed and found able to reverse the malignant properties of EGFR transformed cells in vitro and in vivo. During the reporting period, the designed EGFR ectodomain inhibitor has been tested for inhibition of EGFR phosphorylation and growth of breast cancer cells in vitro and in vivo. The compound has been shown to inhibit EGF induced phosphorylation of EGFR in EGFR overexpressing cells. A strong inhibitory effect of the compound against MDA-MB- 468 cells has been demonstrated in a poly-HEMA assay. The compound effectively inhibited tumor growth in mice with MDA-MB-468 and A431 xenografts and had a moderate effect in MDA-MB-231 xenografts in vivo. Crystallization studies have produced two types of EGFR crystals suitable for soaking experiments with the inhibitory compounds. A number of structural analogs have been designed that have similar antitumor activities, but more favorable pharmacological properties, compared to the lead compound.