Zhou Lu research group and its collaborators of Fudan University School of pharmacy found a new allosteric inhibitor of pgam1

Recently, Zhou Lu Group, School of medicine, Fudan University, together with Shen Ying group, School of medicine, Shanghai Jiaotong University and Chen Hongzhuan group, Shanghai University of traditional Chinese medicine, found that the novel pgam1 allosteric inhibitor has the inhibitory effect on the proliferation and metastasis of non-small cell lung cancer The research results were published in cell metabolism (DOI: 10.1016 / j.cmet 2019.09.014) Pgam1, as one of the important functional enzymes of glycolysis pathway, catalyzes the conversion of 3-pg3 to 2-pg2, which promotes glucose metabolism and energy generation It affects other metabolic pathways by regulating the transformation balance of 3-PG and 2-PG, participates in the synthesis of biomacromolecules in cells and maintains redox homeostasis, and promotes the proliferation and metastasis of tumor cells The results showed that pgam1 was highly expressed in a variety of malignant tumors, including non-small cell lung cancer, and was positively correlated with poor prognosis Therefore, pgam1 can be used as a target to develop inhibitors targeting tumor metabolism A new allosteric inhibitor of pgam1, named hkb99, was obtained by using a variety of technical means and through the optimization of drug design based on structure The inhibitor has the advantages of high selectivity, high activity and low toxicity Research shows that hkb99 blocks the synthesis of biomacromolecules and destroys the redox homeostasis by inhibiting the transformation from 3-PG to 2-PG, which makes non-small cell lung cancer and erlotinib resistant lung cancer cells unable to grow In addition, hkb99 further inhibited the metastasis of NSCLC cells by inhibiting the interaction between pgam1 protein and ACTA2 protein In this study, small molecules interfere with both enzyme and non enzyme functions of protein, which further proves that pgam1 is a potential drug target for lung cancer treatment, and provides a new direction for the development of anti-tumor drugs with new mechanism of action Huang Ke, 2013 Ph.D student of Fudan University School of pharmacy, Liang Qian, 2018 Ph.D student of Shanghai Jiaotong University School of medicine and Zhou ye, 2016 master's degree student are the co first authors of the paper Shen Ying, associate researcher of School of basic medicine of Shanghai Jiaotong University, Zhou Lu, associate professor of School of medicine of Fudan University and Chen Hongzhuan, Professor of Shanghai University of traditional Chinese medicine are the co correspondents of the paper, and the school of medicine of Fudan University is the first unit of the paper Experts from Fudan University School of pharmacy, Shanghai collaborative innovation center of translational medicine, Shanghai Institute of medicine, Chinese Academy of Sciences, National Key Laboratory of oncogene and related genes, Key Laboratory of apoptosis and differentiation, Ministry of education, Department of chemistry, University of Chicago and other units participated in the study The research was supported by grants from NSFC, Shanghai Science and Technology Commission and Shanghai Education Commission Zhou Lu, associate professor of School of pharmacy, Fudan University, has been engaged in the original drug discovery based on the new target of tumor metabolism and the research on the interaction mechanism between target protein and drug molecules for a long time By means of pharmaceutical chemistry and chemical biology, he designed and synthesized small molecule drugs for the important target enzyme pgam1 of tumor metabolic pathway and studied their mechanism of action He has published many papers as the first author or communication in cancer cell, nature chemistry, nature communications and other magazines.