Molecular tools for probing signaling networks of the EGFR protein kinase: a thesis submitted in partial fulfilment of the requirements for the degree of Master of Research

The epidermal growth factor receptor (EGFR) is one of the first and most extensively studied receptor tyrosine protein kinases and a validated drug target. Through protein phosphorylation EGFR orchestrates several signaling pathways that regulate cell growth and proliferation, and aberrant EGFR signaling has been reported in numerous cancer types. Several FDA-approved drugs target the ATP site of EGFR, and new therapeutics are in development that target the signaling partners of oncogenic EGFR. However, resistance is a challenge to overcome, and other EGFR-associated signaling proteins have been shown to confer resistance. Chemical probes may aid the elucidation of EGFR signaling networks for finding improved combination therapies. Here we report the sunthesis of first-generation biotinylated chemical probes 1a-1c targeting EGFR. These probes are based on the 4-aniloquinazoline core structure of gefitinib and erlotinib, two FDA-approved EGFR-targeting drugs. The probes 1a-1c exhibit excellent binding affinities for EGFR (Kd=23-41 nM). These probes are expected to serve as the basis for future development of next-generation multifunctional probes for understanding exogenous EGFR signaling networks.