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An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma.
Wen, Chen-Lei; Huang, Ke; Jiang, Lu-Lu; Lu, Xiong-Xiong; Dai, Yu-Ting; Shi, Min-Min; Tang, Xiao-Mei; Wang, Qing-Bing; Zhang, Xiao-Dan; Wang, Peng-Hui; Li, Hui-Ti; Ruan, Xiao-Xue; Wang, Li-Wen; Wang, Xin-Jing; Wang, Qian; Lu, Wei; Xiang, Xiao-Qiang; Sun, Xun; Xu, Yan-Hui; Lai, Lu-Hua; Zhan, Qian; Li, Hong-Wei; Peng, Cheng-Hong; Chen, Jing; Huang, Jin-Yan; Ye, De-Yong; Chen, Sai-Juan; Chen, Zhu; Li, Min; Fang, Yuan; Shen, Bai-Yong; Zhou, Lu.
Afiliación
  • Wen CL; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Huang K; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Jiang LL; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Lu XX; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Dai YT; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Shi MM; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Tang XM; National Research Center for Translational Medicine, Ruijin Hospital, 200025 Shanghai, China.
  • Wang QB; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Zhang XD; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240 Shanghai, China.
  • Wang PH; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Li HT; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Ruan XX; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Wang LW; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Wang XJ; Department of Interventional Radiology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Wang Q; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Lu W; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Xiang XQ; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Sun X; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Xu YH; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Lai LH; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Zhan Q; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Li HW; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Peng CH; Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, 200032 Shanghai, China.
  • Chen J; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Huang JY; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Ye DY; School of Pharmacy, Fudan University, 201203 Shanghai, China.
  • Chen SJ; Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, 200032 Shanghai, China.
  • Chen Z; College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China.
  • Li M; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Fang Y; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Shen BY; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
  • Zhou L; Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.
Proc Natl Acad Sci U S A ; 116(46): 23264-23273, 2019 11 12.
Article en En | MEDLINE | ID: mdl-31662475
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Fosfoglicerato Mutasa / Carcinoma Ductal Pancreático / Antineoplásicos Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article País de afiliación: China
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Fosfoglicerato Mutasa / Carcinoma Ductal Pancreático / Antineoplásicos Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article País de afiliación: China