The EGFR/ERBB family of tyrosine kinase receptors are related with intracellular communications such as cell proliferation, metabolism, and numerous biological responses. The dysregulation of their signal pathway contributes to development of cancer malignancies. This receptor family is a conventional chemotherapeutic target as well as a diagnostic modality. Especially, the ERBB2, also known as HER2 is prognostic biomarker implicated in about 20% of invasive breast cancer. The HER2 status is a crucial factor to decide the treatment type for patients. Common assays used to measure the activated ERBB level analyze tyrosine phosphorylated substrates or the receptors themselves. However, these lysate-based assay results cannot show the difference between a significant mechanistic value and actual clinical relevance. Fluorescent probes can overcome this current detection limit as they provide real-time readouts with minimum perturbation of living cells. As an effort to develop novel tools for ERBB2 cancer biology, we have generated fluorescent kinase inhibitors targeting ATP binding pocket of ERBB2 by activation states. Our fluorescent kinase inhibitors are capable of identifying the ERBB2(+) cells as well as tracking rapid perturbations of the activation states at the level of individual cells. The significance of our research is that these probes provide fast, cost efficient, and precise detection methodology for breast cancer diagnosis and research. The rational design strategy, synthesis, optical profile, confocal imaging and biochemical evaluations will be presented.

Fluorescent kinase inhibitors: Novel modality for HER2 status of breast cancer cells

254th National Meeting (2017)

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