Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
Proc Natl Acad Sci U S A. 2019 Nov 12;116(46):23264-23273. doi: 10.1073/pnas.1914557116. Epub 2019 Oct 29.
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.
糖酵解酶磷酸甘油酸变位酶 1（PGAM1）通过协调糖酵解和生物合成在癌症代谢中起着关键作用。然而，尚未有针对胰腺导管腺癌（PDAC）的经过充分验证的 PGAM1 抑制剂，PDAC 是全球最致命的恶性肿瘤之一。通过揭示在 50 名患者的队列中升高的 PGAM1 表达与 PDAC 的预后较差具有统计学相关性，我们通过结构导向优化开发了一系列别构 PGAM1 抑制剂。化合物 KH3 通过下调与 PGAM1 表达相关的糖酵解和线粒体呼吸水平，显著抑制各种 PDAC 细胞的增殖。与 PGAM1 耗竭相似，KH3 显著阻碍了高度参与癌症代谢和发展的经典途径。此外，我们在多个 PDAC 原代细胞中观察到治疗后 12 小时多个标志性途径的共享表达谱，其中匹配的患者衍生异种移植（PDX）模型在 2 周的治疗中对 KH3 有类似的反应。PDX 对 KH3 的更好反应与 PGAM1 的更高表达以及对癌症代谢途径的更长/更强抑制有关。总之，我们的研究结果表明了通过抑制 PDAC 中的 PGAM1 靶向癌症代谢的策略。此外，这项工作为代谢治疗在临床实践中的潜在应用提供了“概念验证”。
