Abstract
Phosphoglycerate mutase 1 (PGAM1) coordinates glycolysis and biosynthesis to promote cancer cell proliferation, and is believed to be a promising target for cancer therapy. Herein, based on the anthraquinone scaffold, we synthesized 31 anthraquinone derivatives and investigated the structure−activity relationship (SAR). The 3-substitient of sulfonamide on the anthraquinone scaffold was essential for maintaining potency and the modifications of the hydroxyl of alizarin would cause a sharp decrease in potency. In the meantime, we determined the co-crystal structure of PGAM1 and one of the anthraquinone inhibitors 9i with IC50 value of 0.27 μM. The co-crystal structure revealed that F22, K100 and R116 of PGAM1 were critical residues for the binding of inhibitors which further validated the SAR. Consistent with the crystal structure, a competitive assay illustrated that compound 9i was a noncompetitive inhibitor. In addition, compound 9i effectively restrained different lung cancer cells proliferation in vitro. Taken together, this work provides reliable guide for future development of PGAM1 inhibitors and compound 9i may act as a new leading compound for further optimization.
Highlights
In 1924, Warburg discovered that cancer cells tended to metabolize glucose through aerobic glycolysis rather than oxidative phosphorylation, even if there was sufficient oxygen [1,2].This character of cancer cells was distinct from normal differentiated cells and the phenomenon was thereafter named the “Warburg effect”
Is produced inefficiently in this metabolic pattern, whereas building blocks such as nucleotides, and amino acids are generated in large amounts, satisfying the demands of anabolic biosynthesis which are essential for rapid cell proliferation [9,10,11,12]
Various enzymes playing critical roles in cancer metabolism have been reported, including isocitrate dehydrogenase [13,14,15]. Inhibitors targeting these enzymes have been approved by Food and Drug Administration [14,15] which further demonstrated the potential of modulating cancer metabolism for cancer therapy
Summary
In 1924, Warburg discovered that cancer cells tended to metabolize glucose through aerobic glycolysis rather than oxidative phosphorylation, even if there was sufficient oxygen [1,2]. This character of cancer cells was distinct from normal differentiated cells and the phenomenon was thereafter named the “Warburg effect”. Various enzymes playing critical roles in cancer metabolism have been reported, including isocitrate dehydrogenase [13,14,15]. Inhibitors targeting these enzymes have been approved by Food and Drug Administration [14,15] which further demonstrated the potential of modulating cancer metabolism for cancer therapy
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