Fluorogenic Chemical Tools to Improve Prodrug Treatment Outcomes

Abstract

<b>Abstract ID 13584</b> <b>Poster Board 375</b> Prodrugs are inactive forms of drugs that must be converted to the active drug in the body. This approach is popular as it can improve the absorption of orally administered therapeutics by increasing lipophilicity. A common approach to developing a prodrug is to mask polar hydroxyl groups with esters that can be removed once absorbed by endogenous esterases to release the active drug. Carboxylesterases (CESs) are the predominant esterases that carry out this hydrolytic activation due to their high expression in the liver and intestines. Thus, the pharmacokinetics of the active form of an ester-based prodrug greatly depends on CES activity. The activity of CESs, however, can be drastically different from person to person which has been demonstrated to influence the metabolism and, in some cases, clinical outcomes of patients treated with prodrugs that are substrates for CES1, one of the two main human CESs. The factors that contribute to this have not been fully uncovered despite the established importance of CES1 in drug metabolism. We believe that this lack of knowledge is due to the scarcity and limitations of currently available approaches to study CES1 activity in live samples. To address these challenges, we have developed new fluorogenic chemical tools that can report on CES1 activity in live cells. Subsequently, we demonstrate that these tools can identify potential CES1-mediated drug-drug interactions and can be deployed our tools in a fluorescence microscopy-based approach we created to monitor CES1 sequence-dependent activity variations in live cells. Overall, our chemical tools and approaches can help uncover factors that result in the variability of patient response to treatment with CES1-substrate drugs. We believe that the more detailed understanding of the factors that influence CES1 activity that our chemical tools can provide will lead to better patient outcomes when treated with prodrugs.