Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826, Zhangheng Rd., Shanghai 201203, China.
Molecules. 2019 Feb 27;24(5):845. doi: 10.3390/molecules24050845.
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 with IC 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 was a noncompetitive inhibitor. In addition, compound effectively restrained different lung cancer cells proliferation in vitro. Taken together, this work provides reliable guide for future development of PGAM1 inhibitors and compound may act as a new leading compound for further optimization.
磷酸甘油酸变位酶 1（PGAM1）协调糖酵解和生物合成以促进癌细胞增殖，被认为是癌症治疗的有前途的靶点。在此，基于蒽醌骨架，我们合成了 31 种蒽醌衍生物，并研究了它们的构效关系（SAR）。磺酰胺在蒽醌骨架上的 3-取代基对于保持活性是必不可少的，而茜素的羟基修饰会导致活性急剧下降。同时，我们测定了 PGAM1 与其中一个蒽醌抑制剂的共晶结构，其 IC 值为 0.27 μM。共晶结构表明 PGAM1 的 F22、K100 和 R116 是抑制剂结合的关键残基，进一步验证了 SAR。与晶体结构一致，竞争性测定表明化合物 是一种非竞争性抑制剂。此外，化合物 在体外有效抑制了不同肺癌细胞的增殖。总之，这项工作为未来 PGAM1 抑制剂的开发提供了可靠的指导，化合物 可能作为进一步优化的新先导化合物。
