Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Review Article

Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications

Author(s): Peng Chen, Liang Lou, Bigyan Sharma, Mengchu Li, Chengliang Xie, Fen Yang, Yihang Wu*, Qicai Xiao* and Liqian Gao*

Volume 31, Issue 20, 2024

Published on: 07 September, 2023

Page: [2955 - 2973] Pages: 19

DOI: 10.2174/0929867331666230714144851

Price: $65

Abstract

Metabolic reprogramming of cells, from the normal mode of glucose metabolism named glycolysis, is a pivotal characteristic of impending cancerous cells. Pyruvate kinase M2 (PKM2), an important enzyme that catalyzes the final rate-limiting stage during glycolysis, is highly expressed in numerous types of tumors and aids in development of favorable conditions for the survival of tumor cells. Increasing evidence has suggested that PKM2 is one of promising targets for innovative drug discovery, especially for the developments of antitumor therapeutics. Herein, we systematically summarize the recent advancement on PKM2 modulators including inhibitors and activators in cancer applications. We also discussed the classifications of pyruvate kinases in mammals and the biological functions of PKM2 in this review. We do hope that this review would provide a comprehensive understanding of the current research on PKM2 modulators, which may benefit the development of more potent PKM2-related drug candidates to treat PKM2-associated diseases including cancers in future.

Keywords: PKM2, inhibitors, activators, antitumor, biomedical applications, modulators.

« Previous Next »
[1]
Chaneton, B.; Hillmann, P.; Zheng, L.; Martin, A.C.L.; Maddocks, O.D.K.; Chokkathukalam, A.; Coyle, J.E.; Jankevics, A.; Holding, F.P.; Vousden, K.H.; Frezza, C.; O’Reilly, M.; Gottlieb, E. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature, 2012, 491(7424), 458-462.
[http://dx.doi.org/10.1038/nature11540] [PMID: 23064226]
[2]
Dayton, T.L.; Jacks, T.; Vander Heiden, M.G. PKM 2, cancer metabolism, and the road ahead. EMBO Rep., 2016, 17(12), 1721-1730.
[http://dx.doi.org/10.15252/embr.201643300] [PMID: 27856534]
[3]
Reiss, N.; Kanety, H.; Schlessinger, J. Five enzymes of the glycolytic pathway serve as substrates for purified epidermal-growth-factor-receptor kinase. Biochem. J., 1986, 239(3), 691-697.
[http://dx.doi.org/10.1042/bj2390691] [PMID: 3030270]
[4]
Sale, E.M.; White, M.F.; Kahn, C.R. Phosphorylation of glycolytic and gluconeogenic enzymes by the insulin receptor kinase. J. Cell. Biochem., 1987, 33(1), 15-26.
[http://dx.doi.org/10.1002/jcb.240330103] [PMID: 2434517]
[5]
Xu, D.; Liang, J.; Lin, J.; Yu, C. PKM2: A potential regulator of rheumatoid arthritis via glycolytic and non-glycolytic pathways. Front. Immunol., 2019, 10, 2919.
[http://dx.doi.org/10.3389/fimmu.2019.02919] [PMID: 31921178]
[6]
Presek, P.; Reinacher, M.; Eigenbrodt, E. Pyruvate kinase type M2 is phosphorylated at tyrosine residues in cells transformed by Rous sarcoma virus. FEBS Lett., 1988, 242(1), 194-198.
[http://dx.doi.org/10.1016/0014-5793(88)81014-7] [PMID: 2462512]
[7]
Mazurek, S.; Grimm, H.; Boschek, C.B.; Vaupel, P.; Eigenbrodt, E. Pyruvate kinase type M2: A crossroad in the tumor metabolome. Br. J. Nutr., 2002, 87(S1), S23-S29.
[http://dx.doi.org/10.1079/BJN2001454] [PMID: 11895152]
[8]
Noguchi, T.; Yamada, K.; Inoue, H.; Matsuda, T.; Tanaka, T. The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J. Biol. Chem., 1987, 262(29), 14366-14371.
[http://dx.doi.org/10.1016/S0021-9258(18)47947-1] [PMID: 3654663]
[9]
Lai, Y-J.; Chou, Y-C.; Lin, Y-J.; Yu, M-H.; Ou, Y-C.; Chu, P-W.; Wu, C-C.; Wang, Y-C.; Chao, T-K. Pyruvate kinase M2 expression: A potential metabolic biomarker to differentiate endometrial precancer and cancer that is associated with poor outcomes in endometrial carcinoma. Int. J. Environ. Res. Public Health, 2019, 16(23), 4589.
[http://dx.doi.org/10.3390/ijerph16234589] [PMID: 31756939]
[10]
Kang, Y.P.; Ward, N.P.; DeNicola, G.M. Recent advances in cancer metabolism: A technological perspective. Exp. Mol. Med., 2018, 50(4), 1-16.
[http://dx.doi.org/10.1038/s12276-018-0027-z] [PMID: 29657324]
[11]
Martinez-Outschoorn, U.E.; Peiris-Pagés, M.; Pestell, R.G.; Sotgia, F.; Lisanti, M.P. Cancer metabolism: A therapeutic perspective. Nat. Rev. Clin. Oncol., 2017, 14(1), 11-31.
[http://dx.doi.org/10.1038/nrclinonc.2016.60] [PMID: 27141887]
[12]
Stein, E.M.; DiNardo, C.D.; Pollyea, D.A.; Fathi, A.T.; Roboz, G.J.; Altman, J.K.; Stone, R.M.; DeAngelo, D.J.; Levine, R.L.; Flinn, I.W.; Kantarjian, H.M.; Collins, R.; Patel, M.R.; Frankel, A.E.; Stein, A.; Sekeres, M.A.; Swords, R.T.; Medeiros, B.C.; Willekens, C.; Vyas, P.; Tosolini, A.; Xu, Q.; Knight, R.D.; Yen, K.E.; Agresta, S.; de Botton, S.; Tallman, M.S. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood, 2017, 130(6), 722-731.
[http://dx.doi.org/10.1182/blood-2017-04-779405] [PMID: 28588020]
[13]
Li, J.; Li, S.; Guo, J.; Li, Q.; Long, J.; Ma, C.; Ding, Y.; Yan, C.; Li, L.; Wu, Z.; Zhu, H.; Li, K.K.; Wen, L.; Zhang, Q.; Xue, Q.; Zhao, C.; Liu, N.; Ivanov, I.; Luo, M.; Xi, R.; Long, H.; Wang, P.G.; Chen, Y. Natural Product Micheliolide (MCL) irreversibly activates pyruvate kinase M2 and suppresses leukemia. J. Med. Chem., 2018, 61(9), 4155-4164.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00241] [PMID: 29641204]
[14]
Ding, Y.; Xue, Q.; Liu, S.; Hu, K.; Wang, D.; Wang, T.; Li, Y.; Guo, H.; Hao, X.; Ge, W.; Zhang, Y.; Li, A.; Li, J.; Chen, Y.; Zhang, Q. Identification of parthenolide dimers as activators of pyruvate kinase M2 in xenografts of glioblastoma multiforme in vivo. J. Med. Chem., 2020, 63(4), 1597-1611.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01328] [PMID: 31977207]
[15]
Ma, Q.S.; Yao, Y.; Zheng, Y.C.; Feng, S.; Chang, J.; Yu, B.; Liu, H.M. Ligand-based design, synthesis and biological evaluation of xanthine derivatives as LSD1/KDM1A inhibitors. Eur. J. Med. Chem., 2019, 162, 555-567.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.035] [PMID: 30472603]
[16]
Fang, Y.; Liao, G.; Yu, B. LSD1/KDM1A inhibitors in clinical trials: Advances and prospects. J. Hematol. Oncol., 2019, 12(1), 129.
[http://dx.doi.org/10.1186/s13045-019-0811-9] [PMID: 31801559]
[17]
Wu, G.; Zhao, T.; Kang, D.; Zhang, J.; Song, Y.; Namasivayam, V.; Kongsted, J.; Pannecouque, C.; De Clercq, E.; Poongavanam, V.; Liu, X.; Zhan, P. overview of recent strategic advances in medicinal chemistry. J. Med. Chem., 2019, 62(21), 9375-9414.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00359] [PMID: 31050421]
[18]
Ma, Y.; Frutos-Beltrán, E.; Kang, D.; Pannecouque, C.; De Clercq, E.; Menéndez-Arias, L.; Liu, X.; Zhan, P. Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses. Chem. Soc. Rev., 2021, 50(7), 4514-4540.
[http://dx.doi.org/10.1039/D0CS01084G] [PMID: 33595031]
[19]
Xiang, M.; Zhou, Q.; Shi, Z.; Wang, X.; Li, M.; Jia, Y.; Li, S.; Yang, F.; Wang, W.; Chen, T.; Xu, X.; Sharma, B.; Nie, Y.; Xiao, Q.; Gao, L. A review of light sources and enhanced targeting for photodynamic therapy. Curr. Med. Chem., 2021, 28(31), 6437-6457.
[http://dx.doi.org/10.2174/0929867328666210121122106] [PMID: 33475053]
[20]
Xiao, Q.; Zhu, W.; Feng, W.; Lee, S.S.; Leung, A.W.; Shen, J.; Gao, L.; Xu, C. A review of resveratrol as a potent chemoprotective and synergistic agent in cancer chemotherapy. Front. Pharmacol., 2019, 9, 1534.
[http://dx.doi.org/10.3389/fphar.2018.01534] [PMID: 30687096]
[21]
Xiao, Q.; Mai, B.; Nie, Y.; Yuan, C.; Xiang, M.; Shi, Z.; Wu, J.; Leung, W.; Xu, C.; Yao, S.Q.; Wang, P.; Gao, L. In vitro and in vivo demonstration of ultraefficient and broad-spectrum antibacterial agents for photodynamic antibacterial chemotherapy. ACS Appl. Mater. Interfaces, 2021, 13(10), 11588-11596.
[http://dx.doi.org/10.1021/acsami.0c20837] [PMID: 33656316]
[22]
Xiao, Q.; Lin, H.; Wu, J.; Pang, X.; Zhou, Q.; Jiang, Y.; Wang, P.; Leung, W.; Lee, H.; Jiang, S.; Yao, S.Q.; Gao, L.; Liu, G.; Xu, C. Pyridine-embedded phenothiazinium dyes as lysosome-targeted photosensitizers for highly efficient photodynamic antitumor therapy. J. Med. Chem., 2020, 63(9), 4896-4907.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00280] [PMID: 32267685]
[23]
Sharma, B.; Xie, L.; Yang, F.; Wang, W.; Zhou, Q.; Xiang, M.; Zhou, S.; Lv, W.; Jia, Y.; Pokhrel, L.; Shen, J.; Xiao, Q.; Gao, L.; Deng, W. Recent advance on PTP1B inhibitors and their biomedical applications. Eur. J. Med. Chem., 2020, 199, 112376.
[http://dx.doi.org/10.1016/j.ejmech.2020.112376] [PMID: 32416458]
[24]
Gao, L.; Wang, W.; Wang, X.; Yang, F.; Xie, L.; Shen, J.; Brimble, M.A.; Xiao, Q.; Yao, S.Q. Fluorescent probes for bioimaging of potential biomarkers in Parkinson’s disease. Chem. Soc. Rev., 2021, 50(2), 1219-1250.
[http://dx.doi.org/10.1039/D0CS00115E] [PMID: 33284303]
[25]
Noguchi, T.; Inoue, H.; Tanaka, T. The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J. Biol. Chem., 1986, 261(29), 13807-13812.
[http://dx.doi.org/10.1016/S0021-9258(18)67091-7] [PMID: 3020052]
[26]
Takenaka, M.; Noguchi, T.; Sadahiro, S.; Hirai, H.; Yamada, K.; Matsuda, T.; Imai, E.; Tanaka, T. Isolation and characterization of the human pyruvate kinase M gene. Eur. J. Biochem., 1991, 198(1), 101-106.
[http://dx.doi.org/10.1111/j.1432-1033.1991.tb15991.x] [PMID: 2040271]
[27]
Imamura, K.; Tanaka, T. Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I. Electrophoretic studies. J. Biochem., 1972, 71(6), 1043-1051.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a129852] [PMID: 4342282]
[28]
Netzker, R.; Greiner, E.; Eigenbrodt, E.; Noguchi, T.; Tanaka, T.; Brand, K. Cell cycle-associated expression of M2-type isozyme of pyruvate kinase in proliferating rat thymocytes. J. Biol. Chem., 1992, 267(9), 6421-6424.
[http://dx.doi.org/10.1016/S0021-9258(18)42712-3] [PMID: 1556146]
[29]
Clower, C.V.; Chatterjee, D.; Wang, Z.; Cantley, L.C.; Vander Heiden, M.G.; Krainer, A.R. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc. Natl. Acad. Sci., 2010, 107(5), 1894-1899.
[http://dx.doi.org/10.1073/pnas.0914845107] [PMID: 20133837]
[30]
David, C.J.; Chen, M.; Assanah, M.; Canoll, P.; Manley, J.L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature, 2010, 463(7279), 364-368.
[http://dx.doi.org/10.1038/nature08697] [PMID: 20010808]
[31]
Wang, Z.; Chatterjee, D.; Jeon, H.Y.; Akerman, M.; Vander Heiden, M.G.; Cantley, L.C.; Krainer, A.R. Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J. Mol. Cell Biol., 2012, 4(2), 79-87.
[http://dx.doi.org/10.1093/jmcb/mjr030] [PMID: 22044881]
[32]
Chen, M.; David, C.J.; Manley, J.L. Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins. Nat. Struct. Mol. Biol., 2012, 19(3), 346-354.
[http://dx.doi.org/10.1038/nsmb.2219] [PMID: 22307054]
[33]
Israelsen, W.J.; Vander Heiden, M.G. Pyruvate kinase: Function, regulation and role in cancer. Semin. Cell Dev. Biol., 2015, 43, 43-51.
[http://dx.doi.org/10.1016/j.semcdb.2015.08.004] [PMID: 26277545]
[34]
Zhang, Z.; Deng, X.; Liu, Y.; Liu, Y.; Sun, L.; Chen, F. PKM2, function and expression and regulation. Cell Biosci., 2019, 9(1), 52.
[http://dx.doi.org/10.1186/s13578-019-0317-8] [PMID: 31391918]
[35]
Su, Q.; Luo, S.; Tan, Q.; Deng, J.; Zhou, S.; Peng, M.; Tao, T.; Yang, X. The role of pyruvate kinase M2 in anticancer therapeutic treatments (Review). Oncol. Lett., 2019, 18(6), 5663-5672.
[http://dx.doi.org/10.3892/ol.2019.10948] [PMID: 31788038]
[36]
Erlanson, D.A.; Fesik, S.W.; Hubbard, R.E.; Jahnke, W.; Jhoti, H. Twenty years on: The impact of fragments on drug discovery. Nat. Rev. Drug Discov., 2016, 15(9), 605-619.
[http://dx.doi.org/10.1038/nrd.2016.109] [PMID: 27417849]
[37]
Walsh, M.J.; Brimacombe, K.R.; Veith, H.; Bougie, J.M.; Daniel, T.; Leister, W.; Cantley, L.C.; Israelsen, W.J.; Vander Heiden, M.G.; Shen, M.; Auld, D.S.; Thomas, C.J.; Boxer, M.B. 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett., 2011, 21(21), 6322-6327.
[http://dx.doi.org/10.1016/j.bmcl.2011.08.114] [PMID: 21958545]
[38]
Guo, C.; Linton, A.; Jalaie, M.; Kephart, S.; Ornelas, M.; Pairish, M.; Greasley, S.; Richardson, P.; Maegley, K.; Hickey, M.; Li, J.; Wu, X.; Ji, X.; Xie, Z. Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators. Bioorg. Med. Chem. Lett., 2013, 23(11), 3358-3363.
[http://dx.doi.org/10.1016/j.bmcl.2013.03.090] [PMID: 23622982]
[39]
Lewandowska, U.; Szewczyk, K.; Hrabec, E.; Janecka, A.; Gorlach, S. Overview of metabolism and bioavailability enhancement of polyphenols. J. Agric. Food Chem., 2013, 61(50), 12183-12199.
[http://dx.doi.org/10.1021/jf404439b] [PMID: 24295170]
[40]
Aslan, E.; Guler, C.; Adem, S. In vitro effects of some flavonoids and phenolic acids on human pyruvate kinase isoenzyme M2. J. Enzyme Inhib. Med. Chem., 2016, 31(2), 314-317.
[http://dx.doi.org/10.3109/14756366.2015.1022173] [PMID: 25798688]
[41]
Aslan, E.; Adem, S. In vitro effects of some flavones on human pyruvate kinase isoenzyme M2. J. Biochem. Mol. Toxicol., 2015, 29(3), 109-113.
[http://dx.doi.org/10.1002/jbt.21673] [PMID: 25388478]
[42]
You, L.; Zhu, H.; Wang, C.; Wang, F.; Li, Y.; Li, Y.; Wang, Y.; He, B. Scutellarin inhibits Hela cell growth and glycolysis by inhibiting the activity of pyruvate kinase M2. Bioorg. Med. Chem. Lett., 2017, 27(24), 5404-5408.
[http://dx.doi.org/10.1016/j.bmcl.2017.11.011] [PMID: 29157862]
[43]
Li, R.D.; Zhang, X.; Li, Q.Y.; Ge, Z.M.; Li, R.T. Novel EGFR inhibitors prepared by combination of dithiocarbamic acid esters and 4-anilinoquinazolines. Bioorg. Med. Chem. Lett., 2011, 21(12), 3637-3640.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.096] [PMID: 21570843]
[44]
Duan, Y.C.; Zheng, Y.C.; Li, X.C.; Wang, M.M.; Ye, X.W.; Guan, Y.Y.; Liu, G.Z.; Zheng, J.X.; Liu, H.M. Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole–dithiocarbamate–urea hybrids. Eur. J. Med. Chem., 2013, 64, 99-110.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.058] [PMID: 23644193]
[45]
Ning, X.; Qi, H.; Li, R.; Li, Y.; Jin, Y.; McNutt, M.A.; Liu, J.; Yin, Y. Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase. Eur. J. Med. Chem., 2017, 138, 343-352.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.064] [PMID: 28688274]
[46]
Li, R.; Ning, X.; Zhou, S.; Lin, Z.; Wu, X.; Chen, H.; Bai, X.; Wang, X.; Ge, Z.; Li, R.; Yin, Y. Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators. Eur. J. Med. Chem., 2018, 143, 48-65.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.023] [PMID: 29172082]
[47]
Anastasiou, D.; Yu, Y.; Israelsen, W.J.; Jiang, J.K.; Boxer, M.B.; Hong, B.S.; Tempel, W.; Dimov, S.; Shen, M.; Jha, A.; Yang, H.; Mattaini, K.R.; Metallo, C.M.; Fiske, B.P.; Courtney, K.D.; Malstrom, S.; Khan, T.M.; Kung, C.; Skoumbourdis, A.P.; Veith, H.; Southall, N.; Walsh, M.J.; Brimacombe, K.R.; Leister, W.; Lunt, S.Y.; Johnson, Z.R.; Yen, K.E.; Kunii, K.; Davidson, S.M.; Christofk, H.R.; Austin, C.P.; Inglese, J.; Harris, M.H.; Asara, J.M.; Stephanopoulos, G.; Salituro, F.G.; Jin, S.; Dang, L.; Auld, D.S.; Park, H.W.; Cantley, L.C.; Thomas, C.J.; Vander Heiden, M.G. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat. Chem. Biol., 2012, 8(10), 839-847.
[http://dx.doi.org/10.1038/nchembio.1060] [PMID: 22922757]
[48]
Matsui, Y.; Yasumatsu, I.; Asahi, T.; Kitamura, T.; Kanai, K.; Ubukata, O.; Hayasaka, H.; Takaishi, S.; Hanzawa, H.; Katakura, S. Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator. Bioorg. Med. Chem., 2017, 25(13), 3540-3546.
[http://dx.doi.org/10.1016/j.bmc.2017.05.004] [PMID: 28511909]
[49]
Zhang, Y.; Liu, B.; Wu, X.; Li, R.; Ning, X.; Liu, Y.; Liu, Z.; Ge, Z.; Li, R.; Yin, Y. New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds. Bioorg. Med. Chem., 2015, 23(15), 4815-4823.
[http://dx.doi.org/10.1016/j.bmc.2015.05.041] [PMID: 26081759]
[50]
Liu, B.; Yuan, X.; Xu, B.; Zhang, H.; Li, R.; Wang, X.; Ge, Z.; Li, R. Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators and PKM2 nucleus translocation inhibitors. Eur. J. Med. Chem., 2019, 170, 1-15.
[http://dx.doi.org/10.1016/j.ejmech.2019.03.003] [PMID: 30878825]
[51]
Simon, M.P.; Besmond, C.; Cottreau, D.; Weber, A.; Chaumet-Riffaud, P.; Dreyfus, J.C.; Trépat, J.S.; Marie, J.; Kahn, A. Molecular cloning of cDNA for rat L-type pyruvate kinase and aldolase B. J. Biol. Chem., 1983, 258(23), 14576-14584.
[http://dx.doi.org/10.1016/S0021-9258(17)43902-0] [PMID: 6689021]
[52]
Amin, S.; Yang, P.; Li, Z. Pyruvate kinase M2: A multifarious enzyme in non-canonical localization to promote cancer progression. Biochim. Biophys. Acta Rev. Cancer, 2019, 1871(2), 331-341.
[http://dx.doi.org/10.1016/j.bbcan.2019.02.003] [PMID: 30826427]
[53]
Luo, W.; Semenza, G.L. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol. Metab., 2012, 23(11), 560-566.
[http://dx.doi.org/10.1016/j.tem.2012.06.010] [PMID: 22824010]
[54]
Gwangwa, M.V.; Joubert, A.M.; Visagie, M.H. Crosstalk between the Warburg effect, redox regulation and autophagy induction in tumourigenesis. Cell. Mol. Biol. Lett., 2018, 23(1), 20.
[http://dx.doi.org/10.1186/s11658-018-0088-y] [PMID: 29760743]
[55]
Eigenbrodt, E.; Reinacher, M.; Scheefers-Borchel, U.; Scheefers, H.; Friis, R. Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. Crit. Rev. Oncog., 1992, 3(1-2), 91-115.
[PMID: 1532331]
[56]
Board, M.; Humm, S.; Newsholme, E.A. Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells. Biochem. J., 1990, 265(2), 503-509.
[http://dx.doi.org/10.1042/bj2650503] [PMID: 2302181]
[57]
Lunt, S.Y.; Muralidhar, V.; Hosios, A.M.; Israelsen, W.J.; Gui, D.Y.; Newhouse, L.; Ogrodzinski, M.; Hecht, V.; Xu, K.; Acevedo, P.N.M.; Hollern, D.P.; Bellinger, G.; Dayton, T.L.; Christen, S.; Elia, I.; Dinh, A.T.; Stephanopoulos, G.; Manalis, S.R.; Yaffe, M.B.; Andrechek, E.R.; Fendt, S.M.; Vander Heiden, M.G. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol. Cell, 2015, 57(1), 95-107.
[http://dx.doi.org/10.1016/j.molcel.2014.10.027] [PMID: 25482511]
[58]
Heinrich, R.; Rapoport, T.A. A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. Eur. J. Biochem., 1974, 42(1), 89-95.
[http://dx.doi.org/10.1111/j.1432-1033.1974.tb03318.x] [PMID: 4830198]
[59]
Heinrich, R.; Rapoport, T.A. A linear steady-state treatment of enzymatic chains. Critique of the crossover theorem and a general procedure to identify interaction sites with an effector. Eur. J. Biochem., 1974, 42(1), 97-105.
[http://dx.doi.org/10.1111/j.1432-1033.1974.tb03319.x] [PMID: 4830199]
[60]
Kacser, H.; Burns, J.A. The control of flux. Symp. Soc. Exp. Biol., 1973, 27, 65-104.
[PMID: 4148886]
[61]
Warburg, O. On the origin of cancer cells. Science, 1956, 123(3191), 309-314.
[http://dx.doi.org/10.1126/science.123.3191.309] [PMID: 13298683]
[62]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[63]
Altenberg, B.; Greulich, K.O. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics, 2004, 84(6), 1014-1020.
[http://dx.doi.org/10.1016/j.ygeno.2004.08.010] [PMID: 15533718]
[64]
Wong, N.; Ojo, D.; Yan, J.; Tang, D. PKM2 contributes to cancer metabolism. Cancer Lett., 2015, 356(2 Pt A), 184-191.
[http://dx.doi.org/10.1016/j.canlet.2014.01.031] [PMID: 24508027]
[65]
Lu, Z.; Hunter, T. Metabolic kinases moonlighting as protein kinases. Trends Biochem. Sci., 2018, 43(4), 301-310.
[http://dx.doi.org/10.1016/j.tibs.2018.01.006] [PMID: 29463470]
[66]
Dayton, T.L.; Gocheva, V.; Miller, K.M.; Israelsen, W.J.; Bhutkar, A.; Clish, C.B.; Davidson, S.M.; Luengo, A.; Bronson, R.T.; Jacks, T.; Vander Heiden, M.G. Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma. Genes Dev., 2016, 30(9), 1020-1033.
[http://dx.doi.org/10.1101/gad.278549.116] [PMID: 27125672]
[67]
Hosios, A.M.; Fiske, B.P.; Gui, D.Y.; Vander Heiden, M.G. Lack of evidence for PKM2 protein kinase activity. Mol. Cell, 2015, 59(5), 850-857.
[http://dx.doi.org/10.1016/j.molcel.2015.07.013] [PMID: 26300261]
[68]
Luo, W.; Hu, H.; Chang, R.; Zhong, J.; Knabel, M.; O’Meally, R.; Cole, R.N.; Pandey, A.; Semenza, G.L. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell, 2011, 145(5), 732-744.
[http://dx.doi.org/10.1016/j.cell.2011.03.054] [PMID: 21620138]
[69]
Luo, W.; Semenza, G.L. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget, 2011, 2(7), 551-556.
[http://dx.doi.org/10.18632/oncotarget.299] [PMID: 21709315]
[70]
Zhao, R.; Li, L.; Yang, J. PKM2 affects the development of hepatocellular carcinoma. Int. J. Clin. Exp. Med., 2016, 9(6), 8.
[71]
Yang, W.; Xia, Y.; Hawke, D.; Li, X.; Liang, J.; Xing, D.; Aldape, K.; Hunter, T.; Alfred Yung, W.K.; Lu, Z. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell, 2012, 150(4), 685-696.
[http://dx.doi.org/10.1016/j.cell.2012.07.018] [PMID: 22901803]
[72]
Wang, H.J.; Hsieh, Y.J.; Cheng, W.C.; Lin, C.P.; Lin, Y.; Yang, S.F.; Chen, C.C.; Izumiya, Y.; Yu, J.S.; Kung, H.J.; Wang, W.C. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism. Proc. Natl. Acad. Sci., 2014, 111(1), 279-284.
[http://dx.doi.org/10.1073/pnas.1311249111] [PMID: 24344305]
[73]
Yang, W.; Zheng, Y.; Xia, Y.; Ji, H.; Chen, X.; Guo, F.; Lyssiotis, C.A.; Aldape, K.; Cantley, L.C.; Lu, Z. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat. Cell Biol., 2012, 14(12), 1295-1304.
[http://dx.doi.org/10.1038/ncb2629] [PMID: 23178880]
[74]
Wu, H.; Li, Z.; Yang, P.; Zhang, L.; Fan, Y.; Li, Z. PKM2 depletion induces the compensation of glutaminolysis through β-catenin/c-Myc pathway in tumor cells. Cell. Signal., 2014, 26(11), 2397-2405.
[http://dx.doi.org/10.1016/j.cellsig.2014.07.024] [PMID: 25041845]
[75]
Yang, W.; Xia, Y.; Ji, H.; Zheng, Y.; Liang, J.; Huang, W.; Gao, X.; Aldape, K.; Lu, Z. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature, 2011, 480(7375), 118-122.
[http://dx.doi.org/10.1038/nature10598] [PMID: 22056988]
[76]
Lv, L.; Xu, Y.P.; Zhao, D.; Li, F.L.; Wang, W.; Sasaki, N.; Jiang, Y.; Zhou, X.; Li, T.T.; Guan, K.L.; Lei, Q.Y.; Xiong, Y. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol. Cell, 2013, 52(3), 340-352.
[http://dx.doi.org/10.1016/j.molcel.2013.09.004] [PMID: 24120661]
[77]
Dong, G.; Mao, Q.; Xia, W.; Xu, Y.; Wang, J.; Xu, L.; Jiang, F. PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncol. Lett., 2016, 11(3), 1980-1986.
[http://dx.doi.org/10.3892/ol.2016.4168] [PMID: 26998110]
[78]
Zhu, H.; Wu, J.; Zhang, W.; Luo, H.; Shen, Z.; Cheng, H.; Zhu, X. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. Sci. Rep., 2016, 6(1), 30788.
[http://dx.doi.org/10.1038/srep30788] [PMID: 27492148]
[79]
Gordon, G.J.; Dong, L.; Yeap, B.Y.; Richards, W.G.; Glickman, J.N.; Edenfield, H.; Mani, M.; Colquitt, R.; Maulik, G.; Van Oss, B.; Sugarbaker, D.J.; Bueno, R. Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma. J. Natl. Cancer Inst., 2009, 101(9), 678-686.
[http://dx.doi.org/10.1093/jnci/djp061] [PMID: 19401544]
[80]
Zhou, H.; Chen, C.; Lan, J.; Liu, C.; Liu, X.; Jiang, L.; Wei, F.; Ma, Q.; Dang, G.; Liu, Z. Differential proteomic profiling of chordomas and analysis of prognostic factors. J. Surg. Oncol., 2010, 102(7), 720-727.
[http://dx.doi.org/10.1002/jso.21674] [PMID: 20721957]
[81]
Lim, J.Y.; Yoon, S.O.; Seol, S.Y.; Hong, S.W.; Kim, J.W.; Choi, S.H.; Cho, J.Y. Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer. World J. Gastroenterol., 2012, 18(30), 4037-4043.
[http://dx.doi.org/10.3748/wjg.v18.i30.4037] [PMID: 22912555]
[82]
Li, J.; Yang, Z.; Zou, Q.; Yuan, Y.; Li, J.; Liang, L.; Zeng, G.; Chen, S. PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin. Transl. Oncol., 2014, 16(2), 200-207.
[http://dx.doi.org/10.1007/s12094-013-1063-8] [PMID: 23793810]
[83]
Falkenius, J.; Lundeberg, J.; Johansson, H.; Tuominen, R.; Frostvik-Stolt, M.; Hansson, J.; Egyhazi Brage, S. High expression of glycolytic and pigment proteins is associated with worse clinical outcome in stage III melanoma. Melanoma Res., 2013, 23(6), 452-460.
[http://dx.doi.org/10.1097/CMR.0000000000000027] [PMID: 24128789]
[84]
Hjerpe, E.; Egyhazi Brage, S.; Carlson, J.; Frostvik Stolt, M.; Schedvins, K.; Johansson, H.; Shoshan, M.; Åvall-Lundqvist, E. Metabolic markers GAPDH, PKM2, ATP5B and BEC-index in advanced serous ovarian cancer. BMC Clin. Pathol., 2013, 13(1), 30.
[http://dx.doi.org/10.1186/1472-6890-13-30] [PMID: 24252137]
[85]
Yuan, C.; Li, Z.; Wang, Y.; Qi, B.; Zhang, W.; Ye, J.; Wu, H.; Jiang, H.; Song, L.N.; Yang, J.; Cheng, J. Overexpression of metabolic markers PKM2 and LDH5 correlates with aggressive clinicopathological features and adverse patient prognosis in tongue cancer. Histopathology, 2014, 65(5), 595-605.
[http://dx.doi.org/10.1111/his.12441] [PMID: 24762230]
[86]
Liu, W.R.; Tian, M.X.; Yang, L.X.; Lin, Y.L.; Jin, L.; Ding, Z.B.; Shen, Y.H.; Peng, Y.F.; Gao, D.M.; Zhou, J.; Qiu, S.J.; Dai, Z.; He, R.; Fan, J.; Shi, Y.H. PKM2 promotes metastasis by recruiting myeloid-derived suppressor cells and indicates poor prognosis for hepatocellular carcinoma. Oncotarget, 2015, 6(2), 846-861.
[http://dx.doi.org/10.18632/oncotarget.2749] [PMID: 25514599]
[87]
Chen, Z.; Lu, X.; Wang, Z.; Jin, G.; Wang, Q.; Chen, D.; Chen, T.; Li, J.; Fan, J.; Cong, W.; Gao, Q.; He, X. Co-expression of PKM2 and TRIM35 predicts survival and recurrence in hepatocellular carcinoma. Oncotarget, 2015, 6(4), 2539-2548.
[http://dx.doi.org/10.18632/oncotarget.2991] [PMID: 25576919]
[88]
Hu, W.; Lu, S.X.; Li, M.; Zhang, C.; Liu, L.L.; Fu, J.; Jin, J.T.; Luo, R.Z.; Zhang, C.Z.; Yun, J.P. Pyruvate kinase M2 prevents apoptosis via modulating bim stability and associates with poor outcome in hepatocellular carcinoma. Oncotarget, 2015, 6(9), 6570-6583.
[http://dx.doi.org/10.18632/oncotarget.3262] [PMID: 25788265]
[89]
Zhao, Y.; Shen, L.; Chen, X.; Qian, Y.; Zhou, Q.; Wang, Y.; Li, K.; Liu, M.; Zhang, S.; Huang, X. High expression of PKM2 as a poor prognosis indicator is associated with radiation resistance in cervical cancer. Histol. Histopathol., 2015, 30(11), 1313-1320.
[http://dx.doi.org/10.14670/HH-11-627] [PMID: 25936600]
[90]
Wang, Y.; Zhang, X.; Zhang, Y.; Zhu, Y.; Yuan, C.; Qi, B.; Zhang, W.; Wang, D.; Ding, X.; Wu, H.; Cheng, J. Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma. Cancer Biol. Ther., 2015, 16(6), 839-845.
[http://dx.doi.org/10.1080/15384047.2015.1030551] [PMID: 25970228]
[91]
Ogawa, H.; Nagano, H.; Konno, M.; Eguchi, H.; Koseki, J.; Kawamoto, K.; Nishida, N.; Colvin, H.; Tomokuni, A.; Tomimaru, Y.; Hama, N.; Wada, H.; Marubashi, S.; Kobayashi, S.; Mori, M.; Doki, Y.; Ishii, H. The combination of the expression of hexokinase 2 and pyruvate kinase M2 is a prognostic marker in patients with pancreatic cancer. Mol. Clin. Oncol., 2015, 3(3), 563-571.
[http://dx.doi.org/10.3892/mco.2015.490] [PMID: 26137268]
[92]
Lin, Y.; Liu, F.; Fan, Y.; Qian, X.; Lang, R.; Gu, F.; Gu, J.; Fu, L. Both high expression of pyruvate kinase M2 and vascular endothelial growth factor-C predicts poorer prognosis in human breast cancer. Int. J. Clin. Exp. Pathol., 2015, 8(7), 8028-8037.
[PMID: 26339369]
[93]
Lockney, N.A.; Zhang, M.; Lu, Y.; Sopha, S.C.; Washington, M.K.; Merchant, N.; Zhao, Z.; Shyr, Y.; Chakravarthy, A.B.; Xia, F. Pyruvate Kinase Muscle Isoenzyme 2 (PKM2) expression is associated with overall survival in pancreatic ductal adenocarcinoma. J. Gastrointest. Cancer, 2015, 46(4), 390-398.
[http://dx.doi.org/10.1007/s12029-015-9764-6] [PMID: 26385349]
[94]
Gao, Y.; Xu, D.; Yu, G.; Liang, J. Overexpression of metabolic markers HK1 and PKM2 contributes to lymphatic metastasis and adverse prognosis in Chinese gastric cancer. Int. J. Clin. Exp. Pathol., 2015, 8(8), 9264-9271.
[PMID: 26464675]
[95]
Yu, G.; Yu, W.; Jin, G.; Xu, D.; Chen, Y.; Xia, T.; Yu, A.; Fang, W.; Zhang, X.; Li, Z.; Xie, K. PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma. Mol. Cancer, 2015, 14(1), 193.
[http://dx.doi.org/10.1186/s12943-015-0462-6] [PMID: 26576639]
[96]
Cui, R.; Shi, X-Y. Expression of pyruvate kinase M2 in human colorectal cancer and its prognostic value. Int. J. Clin. Exp. Pathol., 2015, 8(9), 11393-11399.
[PMID: 26617865]
[97]
Mohammad, G.H.; Olde Damink, S.W.M.; Malago, M.; Dhar, D.K.; Pereira, S.P. Pyruvate kinase M2 and lactate dehydrogenase A are overexpressed in pancreatic cancer and correlate with poor outcome. PLoS One, 2016, 11(3), e0151635.
[http://dx.doi.org/10.1371/journal.pone.0151635] [PMID: 26989901]
[98]
Lu, W.; Cao, Y.; Zhang, Y.; Li, S.; Gao, J.; Wang, X.A.; Mu, J.; Hu, Y.P.; Jiang, L.; Dong, P.; Gong, W.; Liu, Y. Up-regulation of PKM2 promote malignancy and related to adverse prognostic risk factor in human gallbladder cancer. Sci. Rep., 2016, 6(1), 26351.
[http://dx.doi.org/10.1038/srep26351] [PMID: 27283076]
[99]
Liu, Z.; Hong, L.; Fang, S.; Tan, G.; Huang, P.; Zeng, Z.; Xia, X.; Wang, X. Overexpression of pyruvate kinase M2 predicts a poor prognosis for patients with osteosarcoma. Tumour Biol., 2016, 37(11), 14923-14928.
[http://dx.doi.org/10.1007/s13277-016-5401-7] [PMID: 27644251]
[100]
Wang, C.; Jiang, J.; Ji, J.; Cai, Q.; Chen, X.; Yu, Y.; Zhu, Z.; Zhang, J. PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer. Sci. Rep., 2017, 7(1), 2886.
[http://dx.doi.org/10.1038/s41598-017-03031-1] [PMID: 28588255]
[101]
Chao, T.K.; Huang, T.S.; Liao, Y.P.; Huang, R.L.; Su, P.H.; Shen, H.Y.; Lai, H.C.; Wang, Y.C. Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer. PLoS One, 2017, 12(7), e0182166.
[http://dx.doi.org/10.1371/journal.pone.0182166] [PMID: 28753677]
[102]
Li, W.; Xu, Z.; Hong, J.; Xu, Y. Expression patterns of three regulation enzymes in glycolysis in esophageal squamous cell carcinoma: Association with survival. Med. Oncol., 2014, 31(9), 118.
[http://dx.doi.org/10.1007/s12032-014-0118-1] [PMID: 25064730]
[103]
Goldberg, M.S.; Sharp, P.A. Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J. Exp. Med., 2012, 209(2), 217-224.
[http://dx.doi.org/10.1084/jem.20111487] [PMID: 22271574]
[104]
Vander Heiden, M.G.; Christofk, H.R.; Schuman, E.; Subtelny, A.O.; Sharfi, H.; Harlow, E.E.; Xian, J.; Cantley, L.C. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol., 2010, 79(8), 1118-1124.
[http://dx.doi.org/10.1016/j.bcp.2009.12.003] [PMID: 20005212]
[105]
Varghese, B.; Swaminathan, G.; Plotnikov, A.; Tzimas, C.; Yang, N.; Rui, H.; Fuchs, S.Y. Prolactin inhibits activity of pyruvate kinase M2 to stimulate cell proliferation. Mol. Endocrinol., 2010, 24(12), 2356-2365.
[http://dx.doi.org/10.1210/me.2010-0219] [PMID: 20962042]
[106]
Zhao, X.; Zhu, Y.; Hu, J.; Jiang, L.; Li, L.; Jia, S.; Zen, K. Shikonin inhibits tumor growth in mice by suppressing pyruvate kinase M2-mediated aerobic glycolysis. Sci. Rep., 2018, 8(1), 14517.
[http://dx.doi.org/10.1038/s41598-018-31615-y] [PMID: 30266938]
[107]
Liu, T.; Li, S.; Wu, L.; Yu, Q.; Li, J.; Feng, J.; Zhang, J.; Chen, J.; Zhou, Y.; Ji, J.; Chen, K.; Mao, Y.; Wang, F.; Dai, W.; Fan, X.; Wu, J.; Guo, C. Experimental study of hepatocellular carcinoma treatment by shikonin through regulating PKM2. J. Hepatocell. Carcinoma, 2020, 7, 19-31.
[http://dx.doi.org/10.2147/JHC.S237614] [PMID: 32110554]
[108]
Yang, W.; Liu, J.; Hou, L.; Chen, Q.; Liu, Y. Shikonin differentially regulates glucose metabolism via PKM2 and HIF1α to overcome apoptosis in a refractory HCC cell line. Life Sci., 2021, 265, 118796.
[http://dx.doi.org/10.1016/j.lfs.2020.118796] [PMID: 33220292]
[109]
Chen, J.; Xie, J.; Jiang, Z.; Wang, B.; Wang, Y.; Hu, X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene, 2011, 30(42), 4297-4306.
[http://dx.doi.org/10.1038/onc.2011.137] [PMID: 21516121]
[110]
Ning, X.; Qi, H.; Li, R.; Jin, Y.; McNutt, M.A.; Yin, Y. Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 126-129.
[http://dx.doi.org/10.1080/14756366.2017.1404591] [PMID: 29185365]
[111]
Shimada, N.; Takasawa, R.; Tanuma, S. Interdependence of GLO I and PKM2 in the metabolic shift to escape apoptosis in GLO I-dependent cancer cells. Arch. Biochem. Biophys., 2018, 638, 1-7.
[http://dx.doi.org/10.1016/j.abb.2017.12.008] [PMID: 29225125]
[112]
Shang, D.; Wu, J.; Guo, L.; Xu, Y.; Liu, L.; Lu, J. Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2. Int. J. Oncol., 2017, 50(5), 1848-1856.
[http://dx.doi.org/10.3892/ijo.2017.3950] [PMID: 28393220]
[113]
Christofk, H.R.; Vander Heiden, M.G.; Wu, N.; Asara, J.M.; Cantley, L.C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature, 2008, 452(7184), 181-186.
[http://dx.doi.org/10.1038/nature06667] [PMID: 18337815]
[114]
Kefas, B.; Comeau, L.; Erdle, N.; Montgomery, E.; Amos, S.; Purow, B. Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro oncol., 2010, 12(11), 1102-1112.
[http://dx.doi.org/10.1093/neuonc/noq080] [PMID: 20667897]
[115]
Zhu, Z.; Tang, G.; Yan, J. MicroRNA-122 regulates docetaxel resistance of prostate cancer cells by regulating PKM2. Exp. Ther. Med., 2020, 20(6), 1.
[http://dx.doi.org/10.3892/etm.2020.9377] [PMID: 33178345]
[116]
Wang, D.; Zhao, C.; Xu, F.; Zhang, A.; Jin, M.; Zhang, K.; Liu, L.; Hua, Q.; Zhao, J.; Liu, J.; Yang, H.; Huang, G. Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2. Theranostics, 2021, 11(6), 2860-2875.
[http://dx.doi.org/10.7150/thno.51797] [PMID: 33456577]
[117]
Mazurek, S. Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells. Int. J. Biochem. Cell Biol., 2011, 43(7), 969-980.
[http://dx.doi.org/10.1016/j.biocel.2010.02.005] [PMID: 20156581]
[118]
Chen, J.; Jiang, Z.; Wang, B.; Wang, Y.; Hu, X. Vitamin K3 and K5 are inhibitors of tumor pyruvate kinase M2. Cancer Lett., 2012, 316(2), 204-210.
[http://dx.doi.org/10.1016/j.canlet.2011.10.039] [PMID: 22154083]
[119]
Scicchitano, B.M.; Sorrentino, S.; Proietti, G.; Lama, G.; Dobrowolny, G.; Catizone, A.; Binda, E.; Larocca, L.M.; Sica, G. Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis. Cancer Cell Int., 2018, 18(1), 136.
[http://dx.doi.org/10.1186/s12935-018-0626-8] [PMID: 30214378]
[120]
Johnson, D.R.; O’Neill, B.P. Glioblastoma survival in the United States before and during the temozolomide era. J. Neurooncol., 2012, 107(2), 359-364.
[http://dx.doi.org/10.1007/s11060-011-0749-4] [PMID: 22045118]
[121]
Chu, L.; Wang, A.; Ni, L.; Yan, X.; Song, Y.; Zhao, M.; Sun, K.; Mu, H.; Liu, S.; Wu, Z.; Zhang, C. Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting. Drug Deliv., 2018, 25(1), 1634-1641.
[http://dx.doi.org/10.1080/10717544.2018.1494226] [PMID: 30176744]
[122]
Hsieh, I.S.; Gopula, B.; Chou, C.C.; Wu, H.Y.; Chang, G.D.; Wu, W.J.; Chang, C.S.; Chu, P.C.; Chen, C.S. Development of novel irreversible pyruvate kinase M2 inhibitors. J. Med. Chem., 2019, 62(18), 8497-8510.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00763] [PMID: 31465224]
[123]
Kung, C.; Hixon, J.; Choe, S.; Marks, K.; Gross, S.; Murphy, E.; DeLaBarre, B.; Cianchetta, G.; Sethumadhavan, S.; Wang, X.; Yan, S.; Gao, Y.; Fang, C.; Wei, W.; Jiang, F.; Wang, S.; Qian, K.; Saunders, J.; Driggers, E.; Woo, H.K.; Kunii, K.; Murray, S.; Yang, H.; Yen, K.; Liu, W.; Cantley, L.C.; Vander Heiden, M.G.; Su, S.M.; Jin, S.; Salituro, F.G.; Dang, L. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem. Biol., 2012, 19(9), 1187-1198.
[http://dx.doi.org/10.1016/j.chembiol.2012.07.021] [PMID: 22999886]
[124]
Parnell, K.M.; Foulks, J.M.; Nix, R.N.; Clifford, A.; Bullough, J.; Luo, B.; Senina, A.; Vollmer, D.; Liu, J.; McCarthy, V.; Xu, Y.; Saunders, M.; Liu, X.H.; Pearce, S.; Wright, K.; O’Reilly, M.; McCullar, M.V.; Ho, K.K.; Kanner, S.B. Pharmacologic activation of PKM2 slows lung tumor xenograft growth. Mol. Cancer Ther., 2013, 12(8), 1453-1460.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0026] [PMID: 23720766]
[125]
Xu, Y.; Liu, X.H.; Saunders, M.; Pearce, S.; Foulks, J.M.; Parnell, K.M.; Clifford, A.; Nix, R.N.; Bullough, J.; Hendrickson, T.F.; Wright, K.; McCullar, M.V.; Kanner, S.B.; Ho, K.K. Discovery of 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide activators of the M2 isoform of pyruvate kinase (PKM2). Bioorg. Med. Chem. Lett., 2014, 24(2), 515-519.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.028] [PMID: 24374270]
[126]
Yacovan, A.; Ozeri, R.; Kehat, T.; Mirilashvili, S.; Sherman, D.; Aizikovich, A.; Shitrit, A.; Ben-Zeev, E.; Schutz, N.; Bohana-Kashtan, O.; Konson, A.; Behar, V.; Becker, O.M. 1-(sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett., 2012, 22(20), 6460-6468.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.054] [PMID: 22963766]
[127]
Iansante, V.; Choy, P.M.; Fung, S.W.; Liu, Y.; Chai, J.G.; Dyson, J.; Del Rio, A.; D’Santos, C.; Williams, R.; Chokshi, S.; Anders, R.A.; Bubici, C.; Papa, S. PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. Nat. Commun., 2015, 6(1), 7882.
[http://dx.doi.org/10.1038/ncomms8882] [PMID: 26258887]
[128]
Rathod, B.; Chak, S.; Patel, S.; Shard, A. Tumor pyruvate kinase M2 modulators: A comprehensive account of activators and inhibitors as anticancer agents. RSC Med. Chem., 2021, 12(7), 1121-1141.
[http://dx.doi.org/10.1039/D1MD00045D] [PMID: 34355179]
[129]
Arora, S.; Joshi, G.; Chaturvedi, A.; Heuser, M.; Patil, S.; Kumar, R. A perspective on medicinal chemistry approaches for targeting pyruvate kinase M2. J. Med. Chem., 2022, 65(2), 1171-1205.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00981] [PMID: 34726055]
[130]
Gorgulla, C.; Boeszoermenyi, A.; Wang, Z.F.; Fischer, P.D.; Coote, P.W.; Padmanabha Das, K.M.; Malets, Y.S.; Radchenko, D.S.; Moroz, Y.S.; Scott, D.A.; Fackeldey, K.; Hoffmann, M.; Iavniuk, I.; Wagner, G.; Arthanari, H. An open-source drug discovery platform enables ultra-large virtual screens. Nature, 2020, 580(7805), 663-668.
[http://dx.doi.org/10.1038/s41586-020-2117-z] [PMID: 32152607]
[131]
Li, Y.; De Luca, R.; Cazzamalli, S.; Pretto, F.; Bajic, D.; Scheuermann, J.; Neri, D. Versatile protein recognition by the encoded display of multiple chemical elements on a constant macrocyclic scaffold. Nat. Chem., 2018, 10(4), 441-448.
[http://dx.doi.org/10.1038/s41557-018-0017-8] [PMID: 29556050]
[132]
Gura, T. DNA helps build molecular libraries for drug testing. Science, 2015, 350(6265), 1139-1140.
[http://dx.doi.org/10.1126/science.350.6265.1139] [PMID: 26785450]
[133]
Mullard, A. DNA tags help the hunt for drugs. Nature, 2016, 530(7590), 367-369.
[http://dx.doi.org/10.1038/530367a] [PMID: 26887498]
[134]
Jee, J.E.; Lim, J.; Ong, Y.S.; Oon, J.; Gao, L.; Choi, H.S.; Lee, S.S. An efficient strategy to enhance binding affinity and specificity of a known isozyme inhibitor. Org. Biomol. Chem., 2016, 14(28), 6833-6839.
[http://dx.doi.org/10.1039/C6OB01104G] [PMID: 27339902]
[135]
Ong, Y.S.; Gao, L.; Kalesh, K.A.; Yu, Z.; Wang, J.; Liu, C.; Li, Y.; Sun, H.; Lee, S.S. Recent advances in synthesis and identification of cyclic peptides for bioapplications. Curr. Top. Med. Chem., 2017, 17(20), 2302-2318.
[http://dx.doi.org/10.2174/1568026617666170224121658] [PMID: 28240181]
[136]
Zerfas, B.L.; Trader, D.J. Monitoring the immunoproteasome in live cells using an activity-based peptide–peptoid hybrid probe. J. Am. Chem. Soc., 2019, 141(13), 5252-5260.
[http://dx.doi.org/10.1021/jacs.8b12873] [PMID: 30862160]
[137]
Jiang, J.; Boxer, M.B.; Vander Heiden, M.G.; Shen, M.; Skoumbourdis, A.P.; Southall, N.; Veith, H.; Leister, W.; Austin, C.P.; Park, H.W.; Inglese, J.; Cantley, L.C.; Auld, D.S.; Thomas, C.J. Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett., 2010, 20(11), 3387-3393.
[http://dx.doi.org/10.1016/j.bmcl.2010.04.015] [PMID: 20451379]
[138]
Rihan, M.; Nalla, L.V.; Dharavath, A.; Patel, S.; Shard, A.; Khairnar, A. Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells. Bioorg. Med. Chem. Lett., 2022, 59, 128539.
[http://dx.doi.org/10.1016/j.bmcl.2022.128539] [PMID: 35007726]
[139]
Patel, S.; Shinde, S.; Patel, S.; Maheshwari, R.; Jariyal, H.; Srivastava, A. Discovery of boronic acid-based potent activators of tumor pyruvate kinase M2 and development of gastroretentive nanoformulation for oral dosing. Bioorg Med Chem Lett., 2021, 42, 128062.
[140]
Patel, S.; Globisch, C.; Pulugu, P.; Kumar, P.; Jain, A.; Shard, A. Novel imidazopyrimidines-based molecules induce tetramerization of tumor pyruvate kinase M2 and exhibit potent antiproliferative profile. Eur. J. Pharm. Sci., 2022, 170, 106112.
[http://dx.doi.org/10.1016/j.ejps.2021.106112] [PMID: 34971746]
[141]
Li, R.; Ning, X.; He, J.; Lin, Z.; Su, Y.; Li, R.; Yin, Y. Synthesis of novel sulfonamide derivatives containing pyridin-3-ylmethyl 4-(benzoyl)piperazine-1-carbodithioate moiety as potent PKM2 activators. Bioorg. Chem., 2021, 108, 104653.
[http://dx.doi.org/10.1016/j.bioorg.2021.104653] [PMID: 33517002]
[142]
Lin, H.; Han, H.; Yang, M.; Wen, Z.; Chen, Q.; Ma, Y.; Wang, X.; Wang, C.; Yin, T.; Wang, X.; Lu, G.; Chen, H.; Qi, J.; Yang, Y. PKM2/PDK1 dual-targeted shikonin derivatives restore the sensitivity of EGFR-mutated NSCLC cells to gefitinib by remodeling glucose metabolism. Eur. J. Med. Chem., 2023, 249(249), 115166.
[http://dx.doi.org/10.1016/j.ejmech.2023.115166] [PMID: 36731272]

Rights & Permissions Print Cite
Article Metrics
52
2
© 2024 Bentham Science Publishers | Privacy Policy