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Targeting the Dimerization of EGFR
Author(s) -
Yang Rob,
Pike Linda,
Marshall Garland
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.792.9
Subject(s) - epidermal growth factor receptor , in silico , egfr inhibitors , tyrosine kinase , small molecule , monoclonal antibody , breast cancer , cancer research , in vitro , receptor tyrosine kinase , drug discovery , computational biology , cancer , kinase , chemistry , biology , medicine , signal transduction , antibody , bioinformatics , microbiology and biotechnology , immunology , biochemistry , gene
It is estimated that one in eight American women will develop breast cancer in her lifetime and a significant number of these cases are due to misregulation of the epidermal growth factor receptor, EGFR. Current drugs based on antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) show promising yet highly variable clinical efficacy. Recent advancements in EGFR‐signaling suggest that these therapeutic limitations are due to underestimation of a complex system that relies on receptor dimerization. Here we report a class of small‐molecule inhibitors that target and disrupt the dimerization in living cells, which contrasts the traditional strategies of developing mAb‐ and TKI‐based inhibitors. Our approach is a top‐down protocol that combines in silico high‐throughput screen of a compound library and in vitro biochemical assays that experimentally test the putative candidates. Several compounds were identified as potent and specific inhibitor against the activation of EGFR in living cells. The discovery, and the on‐going characterization, of these inhibitors offer an alternative class of EGFR‐inhibitors and could serve as the building blocks of novel therapeutics against breast cancer. NIH grant GM68460