Identification of Parthenolide Dimers as Activators of Pyruvate Kinase M2 in Xenografts of Glioblastoma Multiforme in Vivo

被引：46

作者：

Ding, Yahui ^{[1
,2
]}

Xue, Qingqing ^{[1
,2
]}

Liu, Shuo ^{[1
,2
]}

Hu, Kai ^{[3
]}

Wang, Da ^{[1
,2
]}

Wang, Tianpeng ^{[1
,2
]}

Li, Ye ^{[1
,2
]}

Guo, Hongyu ^{[1
,2
]}

Hao, Xin ^{[1
,2
]}

Ge, Weizhi ^{[1
,2
]}

Zhang, Yan ^{[1
,2
]}

Li, Ang ^{[1
,2
]}

Li, Jing ^{[1
,2
]}

Chen, Yue ^{[1
,2
]}

Zhang, Quan ^{[1
,2
]}

机构：

[1] Nankai Univ, State Key Lab Med Chem Biol, Coll Pharm, Tianjin 300353, Peoples R China

[2] Nankai Univ, Tianjin Key Lab Mol Drug Res, Tianjin 300353, Peoples R China

[3] Nankai Univ, Coll Med, Tianjin 3000710, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 04期

基金：

中国国家自然科学基金;

关键词：

CENTRAL-NERVOUS-SYSTEM; SESQUITERPENE LACTONES; CANCER METABOLISM; PRIMARY BRAIN; TUMORS; ISOFORM; PKM2; INHIBITION; CELLS; TEMOZOLOMIDE;

D O I：

10.1021/acs.jmedchem.9b01328

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we detail the discovery of a series of parthenolide dimers as activators of PKM2 and evaluation of their anti-GBM activities. The most promising compound 5 showed high potency to activate PKM2 with an AC(50) value of 15 nM, inhibited proliferation and metastasis, and induced apoptosis of GBM cells. Compound 5 could promote tetramer formation of PKM2 and reduce nucleus translocation of PKM2 in GBM cells without influence on the expression of total PKM2, thereby inhibiting the STAT3 signal pathway in vitro and in vivo. PKM2 knockdown assay demonstrated that the anti-GBM effect of 5 mainly depended on the expression of PKM2 in vitro and in vivo. Compound 16, a prodrug of 5, markedly suppressed U118 tumor xenograft growth and reduced the weight of tumor. On the basis of these investigations, we propose that 16 might be considered as a promising lead compound for discovery of anti-GBM drugs.

引用

页码：1597 / 1611

页数：15

共 53 条

[1] Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis [J].

Anastasiou, Dimitrios ;

Yu, Yimin ;

Israelsen, William J. ;

Jiang, Jian-Kang ;

Boxer, Matthew B. ;

Hong, Bum Soo ;

Tempel, Wolfram ;

Dimov, Svetoslav ;

Shen, Min ;

Jha, Abhishek ;

Yang, Hua ;

Mattaini, Katherine R. ;

Metallo, Christian M. ;

Fiske, Brian P. ;

Courtney, Kevin D. ;

Malstrom, Scott ;

Khan, Tahsin M. ;

Kung, Charles ;

Skoumbourdis, Amanda P. ;

Veith, Henrike ;

Southall, Noel ;

Walsh, Martin J. ;

Brimacombe, Kyle R. ;

Leister, William ;

Lunt, Sophia Y. ;

Johnson, Zachary R. ;

Yen, Katharine E. ;

Kunii, Kaiko ;

Davidson, Shawn M. ;

Christofk, Heather R. ;

Austin, Christopher P. ;

Inglese, James ;

Harris, Marian H. ;

Asara, John M. ;

Stephanopoulos, Gregory ;

Salituro, Francesco G. ;

Jin, Shengfang ;

Dang, Lenny ;

Auld, Douglas S. ;

Park, Hee-Won ;

Cantley, Lewis C. ;

Thomas, Craig J. ;

Heiden, Matthew G. Vander .

NATURE CHEMICAL BIOLOGY, 2012, 8 (10) :839-847

[2] Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses [J].

Anastasiou, Dimitrios ;

Poulogiannis, George ;

Asara, John M. ;

Boxer, Matthew B. ;

Jiang, Jian-kang ;

Shen, Min ;

Bellinger, Gary ;

Sasaki, Atsuo T. ;

Locasale, Jason W. ;

Auld, Douglas S. ;

Thomas, Craig J. ;

Vander Heiden, Matthew G. ;

Cantley, Lewis C. .

SCIENCE, 2011, 334 (6060) :1278-1283

[3] Primary brain tumours in adults [J].

Behin, A ;

Hoang-Xuan, K ;

Carpentier, AF ;

Delattre, JY .

LANCET, 2003, 361 (9354) :323-331

[4] Loss of function of PTEN alters the relationship between glucose concentration and cell proliferation, increases glycolysis, and sensitizes cells to 2-deoxyglucose [J].

Blouin, Marie-Jose ;

Zhao, Yunhua ;

Zakikhani, Mahvash ;

Algire, Carolyn ;

Piura, Esther ;

Pollak, Michael .

CANCER LETTERS, 2010, 289 (02) :246-253

[5] Metabolic profiling of cell growth and death in cancer: applications in drug discovery [J].

Boros, LG ;

Cascante, M ;

Lee, WNP .

DRUG DISCOVERY TODAY, 2002, 7 (06) :364-372

[6] Serine is a natural ligand and allosteric activator of pyruvate kinase M2 [J].

Chaneton, Barbara ;

Hillmann, Petra ;

Zheng, Liang ;

Martin, Agnes C. L. ;

Maddocks, Oliver D. K. ;

Chokkathukalam, Achuthanunni ;

Coyle, Joseph E. ;

Jankevics, Andris ;

Holding, Finn P. ;

Vousden, Karen H. ;

Frezza, Christian ;

O'Reilly, Marc ;

Gottlieb, Eyal .

NATURE, 2012, 491 (7424) :458-+

[7] The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth [J].

Christofk, Heather R. ;

Vander Heiden, Matthew G. ;

Harris, Marian H. ;

Ramanathan, Arvind ;

Gerszten, Robert E. ;

Wei, Ru ;

Fleming, Mark D. ;

Schreiber, Stuart L. ;

Cantley, Lewis C. .

NATURE, 2008, 452 (7184) :230-U74

[8] M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth [J].

Cortes-Cros, Marta ;

Hemmerlin, Christelle ;

Ferretti, Stephane ;

Zhang, Juan ;

Gounarides, John S. ;

Yin, Hong ;

Muller, Alban ;

Haberkorn, Anne ;

Chene, Patrick ;

Sellers, William R. ;

Hofmann, Francesco .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (02) :489-494

[9] Adult glioblastoma multiforme survival in the temozolomide era: A population-based analysis of Surveillance, Epidemiology, and End Results registries [J].

Darefsky, Amy S. ;

King, Joseph T., Jr. ;

Dubrow, Robert .

CANCER, 2012, 118 (08) :2163-2172

[10] Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers [J].

Desai, Shruti ;

Ding, Minming ;

Wang, Bin ;

Lu, Zhimin ;

Zhao, Qi ;

Shaw, Kenna ;

Yung, W. K. Alfred ;

Weinstein, John N. ;

Tan, Ming ;

Yao, Jun .

ONCOTARGET, 2014, 5 (18) :8202-8210

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