Abstract
Upregulation of phosphoglycerate mutase 1 (PGAM1) has been identified as one common phenomenon in a variety of cancers. Inhibition of PGAM1 provides a new promising therapeutic strategy for cancer treatment. Herein, based on our previous work, a series of new N-xanthone benzenesulfonamides were discovered as novel PGAM1 inhibitors. The representative molecule 15h, with an IC50 of 2.1 μM, showed an enhanced PGAM1 inhibitory activity and higher enzyme inhibitory specificity compared to PGMI-004A, as well as a slightly improved antiproliferative activity.
Highlights
IntroductionMetabolic reprogramming has been considered as one of 10 essential hallmarks of cancer cells [1]
Metabolic reprogramming has been considered as one of 10 essential hallmarks of cancer cells [1].This metabolic phenotype is associated with the phenomenon of cancer cells altering their metabolic pathways, including bioenergetics and anabolic biosynthesis, to satisfy the anabolic demands of macromolecular biosynthesis and to maintain cellular redox homeostasis in response to the escalated production of toxic reactive oxygen species (ROS) during cell proliferation [2]
The first identified cancer cell metabolism reprogramming phenomenon was the Warburg effect [3], which refers to cancer cells relying on the high rate of aerobic glycolysis to produce energy rather than the efficient mitochondrial oxidative phosphorylation as in most normal cells [4]
Summary
Metabolic reprogramming has been considered as one of 10 essential hallmarks of cancer cells [1]. The first identified cancer cell metabolism reprogramming phenomenon was the Warburg effect [3], which refers to cancer cells relying on the high rate of aerobic glycolysis to produce energy rather than the efficient mitochondrial oxidative phosphorylation as in most normal cells [4] This specific metabolic pattern in cancer cells serves to supply glycolytic intermediates as building blocks for anabolic biosynthesis of macromolecules, such as RNA/DNA, proteins, and lipids [5]. The molecular mechanism of this function of PGAM1 is that the upregulation of PGAM1 leads to a lower intracellular level of 3PG and a higher intracellular level of 2PG, which results in a high level of pentose phosphate pathway (PPP) flux and activated serine synthesis pathway (SSP), respectively [14,15] This mechanism facilitates the conversion of glycolytic intermediates to the precursors of amino acids and ribose, which are building blocks of DNA/RNA and proteins.
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