Fluorescent Kinase Probes Enabling Identification and Dynamic Imaging of HER2(+) Cells

Abstract

The human epidermal growth factor receptor, EGFR/ERBB/HER, family of receptor tyrosine kinases is central to many signaling pathways and a validated chemotherapy target in multiple cancers. While EGFR/ERBB-targeted therapies, including monoclonal antibodies, e.g., trastuzumab, and small molecule kinase inhibitors, such as lapatinib, have been developed, rapid identification and classification of cancer cells is key to identifying the best treatment regime. We report ERBB2 (also HER2) targeting kinase probes that exhibit a "turn-on" emission response upon binding. These live cell compatible probes differentiate ERBB2(+) cells from low-level, ERBB2(-) cells by targeting the intracellular ATP-binding pocket of ERBB2 with therapeutic inhibitor-like specificity. Beyond kinase expression levels, probe signal is linked to the phosphotyrosine-correlated activation state of the ERBB2 population. Additionally, the rapid signaling capability of the probes can report changes in activation state in live cells providing a unique type of complementary information to immunohistochemical assays of receptor kinase populations.

Design, synthesis and biological evaluation of small molecule fluorescent probes targeting EGFR for tumor detection and treatment

“…14 Fluorescent probes with special chemical structures are essential for investigating protein activity in biological processes and various diseases. 15,16 Especially, the environmentsensitive 1,8-naphthalimide fluorophore possesses outstanding optical properties, high synthesis efficiency and a large Stokes shift. 17,18 Compared to traditional fluorophores with low signal-to-noise ratio and lacking fluorescence switching capabilities, the 1,8-naphthalimide fluorophore excels, playing a vital role in visualizing and facilitating quantitative research on target receptors.…”

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

“…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.…”

M1 Macrophages Enhance Survival and Invasion of Oral Squamous Cell Carcinoma by Inducing GDF15-Mediated ErbB2 Phosphorylation

“…M1-CM also significantly promoted the phosphorylation of ErbB2 (Figure b). To elucidate whether M1-CM-activated AKT and ErK signaling pathways are associated with the ErbB2 receptor, the ErbB2 inhibitor CI-1033 was used. , CI-1033 significantly decreased M1-CM-induced p-AKT and p-ErK expression in SCC25 and CAL27 cells (Figure c). Finally, to explore whether the ErbB2 receptor is also involved in promoting OSCC proliferation, migration, and invasion by M1-CM, SCC25 and CAL27 cells were pretreated with the inhibitor for 2 h and then stimulated with M1-CM.…”