Abstract
A fluorescent probe targeting the ERBB2 receptor tyrosine was designed, synthesized and evaluated as reporter of ERBB2 dynamics in overexpressing BT474, i.e. Her2(+), cells. Two cyanoquinazoline (CQ) probes modeled after type-I (CQ1) or active state and type-II (CQ2) or inactive state inhibitors were designed and synthesized with extended π systems that impart binding-induced, turn-on fluorescence. Solution spectroscopy revealed that CQ1 exhibited attractive photophysical properties and displayed turn-on emission in the presence of purified, soluble ERBB2 kinase domain, while CQ2 was found to be non-emissive, likely due to quenching via a photoinduced electron transfer mechanism. Live cell imaging with CQ1 revealed that this probe targeted an intracellular population of ERBB2, which increased following treatment with type-I inhibitors, gefinitib and canertinib, but showed no response to type-II inhibitors. CQ1 thus provides a novel means of imaging the dynamic response of ERBB2(+) cells to kinase inhibitors.
Original language | English (US) |
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Pages (from-to) | 6016-6023 |
Number of pages | 8 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 25 |
Issue number | 21 |
DOIs | |
State | Published - Nov 1 2017 |
Keywords
- EGFR
- ERBB
- Fluorescent probe
- Kinase inhibitor
- Receptor tyrosine kinase
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry