Synthesis and biological evaluation of anthraquinone derivatives as allosteric phosphoglycerate mutase 1 inhibitors for cancer treatment

European Journal of Medicinal Chemistry
Ke HuangLu Zhou

Abstract

Phosphoglycerate mutase 1 (PGAM1) coordinates glycolysis, pentose phosphate pathway, and serine synthesis to promote tumor growth through the regulation of its substrate 3-phosphoglycerate (3 PG) and product 2-phosphoglycerate (2 PG). Herein, based on our previously reported PGAM1 inhibitor PGMI-004A, we have developed anthraquinone derivatives as novel allosteric PGAM1 inhibitors and the structure-activity relationship (SAR) was investigated. In addition, we determined the co-crystal structure of PGAM1 and the inhibitor 8g, demonstrating that the inhibitor was located at a novel allosteric site. Among the derivatives, compound 8t was selected for further study, with IC50 values of 0.25 and approximately 5 μM in enzymatic and cell-based assays, respectively. Mechanistically, compound 8t reduced the glycolysis and oxygen consumption rate in cancer cells, which led to decreased adenosine 5'-triphosphate (ATP) production and subsequent 5' adenosine monophosphate-activated protein kinase (AMPK) activation. The inhibitor 8t also exhibited good efficacy in delaying tumor growth in H1299 xenograft model without obvious toxicity. Taken together, this proof-of-principle work further validates PGAM1 as a potential target for cancer thera...Continue Reading

Citations

Mar 17, 2020·Future Medicinal Chemistry·Wei TianHuaxin Hou
Jun 4, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nafisa S SirazhetdinovaElvira E Shults
Jan 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Chunqiong LiRugang Zhong
Feb 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaolan ChenNa Zhang
Oct 23, 2020·Life Sciences·Majid GhanavatNajmaldin Saki
Jul 2, 2021·BioMed Research International·Muhammad Mazhar FareedSuliman A Alsagaby
Feb 19, 2020·ACS Chemical Biology·Xiaodan ZhangLu Zhou

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