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Light-Activatable Photocaged UNC2025 for Triggering TAM Kinase Inhibition in Bladder Cancer
Chloé Breton-Patient1,2, Sébastien Billotte3, Patricia Duchambon1,2
1Institut Curie, Université PSL CNRS UMR9187, Inserm U119, 91400, Orsay, France.
Abstract:
Photopharmacology is an emerging field that utilizes photo-responsive molecules to enable control over the activity of a drug using light. The aim is to limit the therapeutic action of a drug at the level of diseased tissues and organs. Considering the well-known implications of protein kinases in cancer and the therapeutic issues associated with protein kinase inhibitors, the photopharmacology is seen as an innovative and alternative solution with great potential in oncology. In this context, we developed the first photocaged TAM kinase inhibitors based on UNC2025, a first-in-class small molecule kinase inhibitor. These prodrugs showed good stability in biologically relevant buffer and rapid photorelease of the photoremovable protecting group upon UV-light irradiation (<10 min.). These light-activatable prodrugs led to a 16-fold decrease to a complete loss of kinase inhibition, depending on the protein and the position at which the coumarin-type phototrigger was introduced. The most promising candidate was the N,O-dicaged compound, showing the superiority of having two photolabile protecting groups on UNC2025 for being entirely inactive on TAM kinases. Under UV-light irradiation, the N,O-dicaged compound recovered its inhibitory potency in enzymatic assays and displayed excellent antiproliferative activity in RT112 cell lines.
Insights
Photopharmacology uses light-activated prodrugs to control drug activity. Researchers developed photocaged TAM kinase inhibitors that become active upon UV light exposure, showing potential for targeted cancer therapy.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Photopharmacology offers precise control over drug activity using light.
- Protein kinase inhibitors are crucial in cancer therapy but face challenges.
- Targeting kinases in cancer requires innovative solutions like photopharmacology.
Purpose of the Study:
- To develop novel photocaged TAM kinase inhibitors for targeted cancer treatment.
- To investigate the light-induced activation of these prodrugs.
- To evaluate their efficacy in enzymatic assays and cell-based models.
Main Methods:
- Development of photocaged TAM kinase inhibitors based on UNC2025.
- Assessment of prodrug stability in biological buffers.
- Evaluation of photorelease kinetics upon UV-light irradiation.
- Enzymatic assays to measure kinase inhibition.
- Cell-based assays to determine antiproliferative activity.
Main Results:
- Developed stable photocaged TAM kinase inhibitors with rapid photorelease (<10 min).
- Achieved significant reduction or complete loss of kinase inhibition until UV-light activation.
- Identified an N,O-dicaged UNC2025 derivative as highly effective, inactive until light exposure.
- Demonstrated recovery of inhibitory potency and antiproliferative activity upon UV irradiation in RT112 cell lines.
Conclusions:
- Photocaged TAM kinase inhibitors represent a promising photopharmacological approach for oncology.
- The N,O-dicaged UNC2025 derivative shows potential for light-controlled cancer therapy.
- This strategy enables precise spatial and temporal control over kinase inhibition.
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