Development of Anthraquinone Analogues as Phosphoglycerate Mutase 1 Inhibitors

• Main Authors: Ke Huang, Lulu Jiang, Huiti Li, Deyong Ye, Lu Zhou
• Format: Article
• Language: English
• Published: MDPI AG 2019-02-01
• Series: Molecules
• Subjects: phosphoglycerate mutase 1; anthraquinone inhibitors; co-crystal structure; cancer treatment
• Online Access: https://www.mdpi.com/1420-3049/24/5/845

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&#8722;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 <b>9i</b> with IC₅₀ value of 0.27 &#956;M. 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 <b>9i</b> was a noncompetitive inhibitor. In addition, compound <b>9i</b> effectively restrained different lung cancer cells proliferation in vitro. Taken together, this work provides reliable guide for future development of PGAM1 inhibitors and compound <b>9i</b> may act as a new leading compound for further optimization.