Synthesis and photophysical properties of a fluorescent cyanoquinoline probe for profiling ERBB2 kinase inhibitor response

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 21; pp. 6016 - 6023
• Main Authors: Lee, Heajin, Landgraf, Ralf, Wilson, James N.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2017; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; EGFR; ERBB; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - chemistry; Fluorescent Dyes - pharmacology; Fluorescent probe; Humans; Kinase inhibitor; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Photochemical Processes; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Quantum Theory; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Receptor tyrosine kinase; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; Receptor tyrosine kinase; Kinase inhibitor; ERBB; EGFR; Fluorescent probe; GEFITINIB; CANCER CELLS; HETERODIMER FORMATION; ENDOCYTOSIS; CHEMOTHERAPY; LUNG-CANCER; IN-VITRO; UBIQUITYLATION; RESISTANCE; DEGRADATION
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.09.034

[Display omitted] 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.