Stimuli-responsive Fluorogenic Prodrugs of Potent Inhibitors Targeting Overexpressed Metabolic Enzymes in Cancer

Abstract

Cancer cells are characterized by rapid, uncontrolled proliferation and rely on altered metabolic pathways to meet the heightened bioenergetic and biogenic demands required for tumour initiation, progression, and invasion. This metabolic reprogramming leads to the overexpression of specific metabolic enzymes that drive pathway-specific alterations to support tumour growth, survival and proliferation. For instance, cancer cells depend on aldose reductase (AR)-mediated glucose metabolism for proliferation, thymidylate synthase (TS)-mediated thymidylate biosynthesis and topoisomerase (Topo)-mediated DNA relaxation to facilitate faster DNA replication. Although specific inhibitors targeting many metabolic enzymes are widely used as chemotherapeutic agents/drugs, their clinical efficacy is often limited and compromised due to the lack of selectivity for cancer cells, poor pharmacokinetics, dose-related toxicities and the development of chemoresistance. Moreover, glutathione-S-transferases (GSTs), phase II metabolic enzymes frequently overexpressed in cancer cells, contribute to chemoresistance and thus represent an additional attractive therapeutic target. Recently, significant research efforts have been made on developing various stimuli-responsive prodrugs that can selectively target enzymes overexpressed in cancer cells to enhance therapeutic efficacy. In this review, we highlight the importance of targeting four key metabolic enzymes from distinct metabolic pathways and discuss on the recent developments of stimuli-responsive turn-on fluorogenic prodrugs of those specific enzyme inhibitors for achieving enhanced selectivity, improved anticancer efficacies, reduced off-target side effects and for enabling real-time non-invasive monitoring of the drug delivery with the turn-on fluorescence read-out. The insights presented herein highlights the potential of stimuli-responsive fluorogenic prodrug strategies as a promising approach for modulating cancer metabolism and improving anticancer therapy.