Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications


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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.

About the authors

Peng Chen

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University

Email: info@benthamscience.net

Liang Lou

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University

Email: info@benthamscience.net

Bigyan Sharma

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University

Email: info@benthamscience.net

Mengchu Li

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University

Email: info@benthamscience.net

Chengliang Xie

School of Pharmaceutical Sciences (Shenzhen), henzhen Campus of Sun Yat-Sen University

Email: info@benthamscience.net

Fen Yang

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen Universit

Email: info@benthamscience.net

Yihang Wu

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University

Author for correspondence.
Email: info@benthamscience.net

Qicai Xiao

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University

Author for correspondence.
Email: info@benthamscience.net

Liqian Gao

School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University

Author for correspondence.
Email: info@benthamscience.net

References

  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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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-benzodimidazol-1-yl)methyl)-4H-pyrido1,2-apyrimidin-4-ones as novel PKM2 activators. Bioorg. Med. Chem. Lett., 2013, 23(11), 3358-3363. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1126/science.350.6265.1139 PMID: 26785450
  133. Mullard, A. DNA tags help the hunt for drugs. Nature, 2016, 530(7590), 367-369. doi: 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. doi: 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. doi: 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. doi: 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 thieno3,2-bpyrrole3,2-dpyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett., 2010, 20(11), 3387-3393. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1016/j.ejmech.2023.115166 PMID: 36731272

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