Light‐Activatable Photocaged UNC2025 for Triggering TAM Kinase Inhibition in Bladder Cancer

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.

All-photonic kinase inhibitors: light-controlled release-and-report inhibition

“…The external control of kinase inhibition has gained increasing attention of late, in which both reversible and irreversible photoactivation of kinase inhibition have been achieved. 4–12 Photocaging has been a popular approach whereby a photolabile protecting moiety is strategically introduced onto a kinase inhibitor to prevent key interactions with their target enzyme. Inhibitory activity is only restored upon exposure to light and concomitant liberation of the active compound.…”

“…The majority of photocaged kinase inhibitors reported to date are reliant on UV light to achieve photoactivation, which limits their use in cellular contexts. 4–9 While the use of fluorescence caging groups that exhibit OFF–ON diagnostic changes in emission upon decaging have been employed to monitor the photorelease of caged substrates in a cellular environment, 13–17 the use of a ‘reporting mechanism’ for both photoactivation and binding of the decaged active inhibitor to the target kinase has yet to be fully explored.…”