An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma

作者：Chenlei Wen, Ke Huang, Lulu Jiang, Xiongxiong Lu, Yuting Dai, Min-Min Shi, Xiao-Mei Tang, Qingbing Wang, Xiaodan Zhang, Peng‐Hui Wang, Huiti Li, Xiaoxue Ruan, Liwen Wang, Xinjing Wang, Qian Wang, Wei Lü, Xiaoqiang Xiang, Xun Sun, Yanhui Xu, Luhua Lai, Qian Zhan, Hongwei Li, Chenghong Peng, Jing Chen, Jin-Yan Huang, Deyong Ye, Sai‐Juan Chen, Chen Zhu, Min Li, Yuan Fang, Baiyong Shen, Lu Zhou · 发表于：Proceedings of the National Academy of Sciences · 年份：2019 · DOI：10.1073/pnas.1914557116 · 被引用次数：67 · 研究领域：Cancer, Hypoxia, and Metabolism、Pancreatic and Hepatic Oncology Research、Epigenetics and DNA Methylation

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided "proof of concept" for the potential application of metabolic treatment in clinical practice.