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Simple Summary: This review highlights the recent advances in the development and application of dual function kinase inhibitors that also bear fluorescent properties (fluorescent kinase inhibitors), thus can be used as theranostics in the field of cancer. This is a rapidly growing field with significant potential for cancer therapy and diagnosis. This work mainly focuses on the key design principles that guide the development of these multifunctional compounds, emphasizing the integration of essential components such as the kinase cytotoxic warhead, the fluorophore, the linkers, and additional modular elements to enhance the efficacy of the final assembled compound. We anticipate this review to propel the advancement of this field by improving the understanding of the design principles and ultimately leading to the development of more effective tools for the concurrent diagnosis and treatment of cancer. Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores. [ABSTRACT FROM AUTHOR]

There is a clear need to develop photostable chromophores for bioimaging with respect to the classically utilized green fluorescent dye fluorescein. Along these lines, we utilized a phosphorescent carboxy-substituted ruthenium(II) polypyridyl [Ru(bipy)2(mcb)]2+ (bipy = 2,2′-bipyridyl and mcb = 4-carboxy-4′-methyl-2,2′-bipyridyl) complex. We developed two luminescent peptide conjugates of the cell-penetrating peptide Tat48–60 consisting of either [Ru(bipy)2(mcb)]2+ or 5(6)-carboxyfluorescein (5(6)-FAM) tethered on the Lys50 of the peptide through amide bond. We confirmed the efficient cellular uptake of both bioconjugates in HeLa cells by confocal microscopy and flow cytometry and proved that the ruthenium-based chromophore possesses enhanced photostability compared to a 5(6)-FAM-based peptide, after continuous laser scanning. Furthermore, we designed and developed a luminescent agent with high photostability, based on the ruthenium core, that could be selectively localized in cancer cells overexpressing the GnRH receptor (GnRH-R). To achieve this, we took advantage of the tumor-homing character of D -Lys6-GnRH which selectively recognizes the GnRH-R. The [Ru(bipy)2(mcb)]2+- D -Lys6-GnRH peptide conjugate was synthesized, and its cellular uptake was evaluated through flow cytometric analysis and live-cell imaging in HeLa and T24 bladder cancer cells as negative and positive controls of GnRH-R, respectively. Besides the selective targeting that the specific conjugate could offer, we also recorded high internalization levels in T24 bladder cancer cells. The ruthenium(II) polypyridyl peptide-based conjugates we developed is an intriguing approach that offers targeted cell imaging in the Near Infrared region, and simultaneously paves the way for further advancements in the dynamic studies on cellular imaging. [ABSTRACT FROM AUTHOR]