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

Lee, Heajin; Landgraf, Ralf; Wilson, James N.

doi:10.1016/j.bmc.2017.09.034

Cited by 8 publications

(3 citation statements)

References 33 publications

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“…Many different approaches have been reported to develop HER1 and HER2 single-targeted theranostic bioimaging probes. Among these achievements, genetically encoded fluorescent biosensors and antibody- or peptidomimetics-mediated EGFR diagnostic tracers have continued to make significant progress in the field as many of the antibody- or peptide-coupled positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging agents have been successfully developed and tested in different stages of clinical trials. − Conversely, despite the generation and evaluation of numerous novel TKIs, there are only a limited number of reports on nongenetic and nonpeptide small-molecule bioprobes that target TKs or their cell surface receptors. − Yet, there were no reports, to our knowledge, on HER1/HER2 dual-targeted small-molecule imaging agents.…”

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confidence: 99%

Discovery of Nonpeptide, Reversible HER1/HER2 Dual-Targeting Small-Molecule Inhibitors as Near-Infrared Fluorescent Probes for Efficient Tumor Detection, Diagnostic Imaging, and Drug Screening

Liu¹,

Song²,

Gao³

et al. 2018

Anal. Chem.

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The abnormal expression of epidermal growth factor receptors HER1(EGFR) and HER2 is strongly associated with cancer invasion, metastasis, and angiogenesis. Their molecular detection is mainly executed using genetically encoded or antibody-based diagnostic tracers, but no dualtargeting small-molecule bioprobe has been achieved. Here, we report the novel small-molecule fluorescent probes Cy3-AFTN and Cy5-AFTN as potent dual-targeting inhibitors for efficient detection of HER1/HER2 expression in cancer cells and in vivo tumor diagnostic imaging. Unlike the irreversible HER1/HER2 inhibitors, Cy3-AFTN and Cy5-AFTN were designed as reversible/noncovalent probes based on the clinical drug afatinib, by making the molecule structurally impossible for receptor-mediated Michael additions. The synthesized probes were validated with live cell fluorescence imaging, flow cytometry and confocal-mediated competitive binding inhibition, molecular docking study, and in vivo xenograft tumor detection. The probes are competitively replaceable by other HER1/HER2 inhibitors; thus, they are potentially useful in fluorometric high-throughput screening for drug discovery.

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mentioning

confidence: 99%

Discovery of Nonpeptide, Reversible HER1/HER2 Dual-Targeting Small-Molecule Inhibitors as Near-Infrared Fluorescent Probes for Efficient Tumor Detection, Diagnostic Imaging, and Drug Screening

Liu¹,

Song²,

Gao³

et al. 2018

Anal. Chem.

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“…However, fixation is associated with disruption of membrane structures, which can give rise to significant artifacts in imaging: the localization of the probe before and after fixation may differ drastically. Therefore, importance of fluorogenic dyes and probes that gain photoluminescence upon binding to PK has been recognized in recent years [72,84,163,[182][183][184].…”

Section: Class 3amentioning

confidence: 99%

Dissection of Protein Kinase Pathways in Live Cells Using Photoluminescent Probes: Surveillance or Interrogation?

2018

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Protein kinases catalyze phosphorylation, a small yet crucial modification that affects participation of the substrate proteins in the intracellular signaling pathways. The activity of 538 protein kinases encoded in human genome relies upon spatiotemporally controlled mechanisms, ensuring correct progression of virtually all physiological processes on the cellular level-from cell division to cell death. The aberrant functioning of protein kinases is linked to a wide spectrum of major health issues including cancer, cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, etc. Hence, significant effort of scientific community has been dedicated to the dissection of protein kinase pathways in their natural milieu. The combination of recent advances in the field of light microscopy, the wide variety of genetically encoded or synthetic photoluminescent scaffolds, and the techniques for intracellular delivery of cargoes has enabled design of a plethora of probes that can report activation of target protein kinases in human live cells. The question remains: how much do we bias intracellular signaling of protein kinases by monitoring it? This review seeks answers to this question by analyzing different classes of probes according to their general structure, mechanism of recognition of biological target, and optical properties necessary for the reporting of intracellular events.

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“…[9] Thea berrant regulation of kinase enzymes is associated with virtually all major disease areas and are therefore regarded as important drug targets. [10] Despite the advantages of fluorescence imaging in live cells,there are only ahandful of examples in which fluorescent kinase inhibitors have been employed as at ool to study kinase inhibition in ac ellular setting, [11] while even fewer have been utilised for in vivo imaging studies. [12] In light of this,w ed escribe herein the design, synthesis, and photophysical as well as the biological characterisation of small prodan-based ATP-competitive kinase inhibitors ( Figure 1).…”

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confidence: 99%

A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding

et al. 2019

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The development of afluorescent LCK inhibitor that exhibits favourable solvatochromic properties upon binding the kinase is described. Fluorescent properties were realised through the inclusion of aprodan-derived fluorophore into the pharmacophore of an ATP-competitive kinase inhibitor. Fluorescence titration experiments demonstrate the solvatochromic properties of the inhibitor,inwhichdramatic increase in emission intensity and hypsochromic shift in emission maxima are clearly observed upon binding LCK. Microscopy experiments in cellular contexts together with flowc ytometry show that the fluorescence intensity of the inhibitor correlates with the LCK concentration. Furthermore,m ultiphoton microscopye xperiments demonstrate both the rapid cellular uptake of the inhibitor and that the two-photon cross section of the inhibitor is amenable for excitation at 700 nm. Small molecule bioactives that exhibit innate fluorescent properties serve as highly valuable tools to probe fundamental events in healthy and diseased cells and tissue.Even more so are those that exhibit diagnostic changes in their emissive properties (i.e.changes in fluorescence intensity or colour) in concert with binding to their respective biomolecular target. [1]

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

Cited by 8 publications

References 33 publications

Discovery of Nonpeptide, Reversible HER1/HER2 Dual-Targeting Small-Molecule Inhibitors as Near-Infrared Fluorescent Probes for Efficient Tumor Detection, Diagnostic Imaging, and Drug Screening

Discovery of Nonpeptide, Reversible HER1/HER2 Dual-Targeting Small-Molecule Inhibitors as Near-Infrared Fluorescent Probes for Efficient Tumor Detection, Diagnostic Imaging, and Drug Screening

Dissection of Protein Kinase Pathways in Live Cells Using Photoluminescent Probes: Surveillance or Interrogation?

A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding

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