The Evolution of Fluorescein into A Potential Theranostic Tool.

Recent advances in drug discovery and development have been marked by the emergence of new modalities, including small molecule theranostic agents. While initial results from clinical trials have been promising, modern detectable inhibitors are still in an early stage of development. In this study, we present a strategy for chemically evolving a fluorescent imaging agent into a potent therapeutic entity, which not only retains its properties but also enhances its inhibition and detection applicability. By utilizing 15-LOX-1 as a model system, we leverage prior knowledge of its inhibitors to rationally functionalize fluorescein, enabling the targeted and highly efficient synthesis of over 20 derivatives across four different scaffolds. This approach ultimately led to the development of a potent, cell-permeable inhibitor that effectively engages its target in live cells and enables real-time visualization. These findings validate our new strategy for the development of small molecule diagnostic modulators, paving the way for application in other targets as well.