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Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors.

Lin H, Zeng J, Xie R, Schulz MJ, Tedesco R, Qu J, Erhard KF, Mack JF, Raha K, Rendina AR, Szewczuk LM, Kratz PM, Jurewicz AJ, Cecconie T, Martens S, McDevitt PJ, Martin JD, Chen SB, Jiang Y, Nickels L, Schwartz BJ, Smallwood A, Zhao B, Campobasso N, Qian Y, Briand J, Rominger CM, Oleykowski C, Hardwicke MA, Luengo JI
ACS Med Chem Lett 7 217-22 (2016)
Related entries: 5hex, 5hg1

Cited: 34 times
EuropePMC logo PMID: 26985301

Abstract

A novel series of potent and selective hexokinase 2 (HK2) inhibitors, 2,6-disubstituted glucosamines, has been identified based on HTS hits, exemplified by compound 1. Inhibitor-bound crystal structures revealed that the HK2 enzyme could adopt an "induced-fit" conformation. The SAR study led to the identification of potent HK2 inhibitors, such as compound 34 with greater than 100-fold selectivity over HK1. Compound 25 inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via (13)CNMR measurement of [3-(13)C]lactate produced from [1,6-(13)C2]glucose added to the cell culture.

Reviews - 5hfu mentioned but not cited (1)

  1. New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology. Sandhu G, Thelma BK. Front Immunol 13 834247 (2022)


Reviews citing this publication (7)

  1. Targeting cancer metabolism in the era of precision oncology. Stine ZE, Schug ZT, Salvino JM, Dang CV. Nat Rev Drug Discov 21 141-162 (2022)
  2. Exploiting Metabolic Vulnerabilities of Cancer with Precision and Accuracy. Wolpaw AJ, Dang CV. Trends Cell Biol 28 201-212 (2018)
  3. Competitive glucose metabolism as a target to boost bladder cancer immunotherapy. Afonso J, Santos LL, Longatto-Filho A, Baltazar F. Nat Rev Urol 17 77-106 (2020)
  4. New strategies for targeting glucose metabolism-mediated acidosis for colorectal cancer therapy. Wang G, Wang JJ, Yin PH, Xu K, Wang YZ, Shi F, Gao J, Fu XL. J Cell Physiol 234 348-368 (2018)
  5. Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics. Ingram DK, Roth GS. Geroscience 43 1159-1169 (2021)
  6. Role of Bladder Cancer Metabolic Reprogramming in the Effectiveness of Immunotherapy. Scholtes MP, de Jong FC, Zuiverloon TCM, Theodorescu D. Cancers (Basel) 13 288 (2021)
  7. Human Triosephosphate Isomerase Is a Potential Target in Cancer Due to Commonly Occurring Post-Translational Modifications. Enríquez-Flores S, De la Mora-De la Mora I, García-Torres I, Flores-López LA, Martínez-Pérez Y, López-Velázquez G. Molecules 28 6163 (2023)

Articles citing this publication (26)

  1. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR, Hay N. Nat Commun 9 446 (2018)
  2. Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2. Li W, Zheng M, Wu S, Gao S, Yang M, Li Z, Min Q, Sun W, Chen L, Xiang G, Li H. J Exp Clin Cancer Res 36 58 (2017)
  3. Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation. Tech K, Tikunov AP, Farooq H, Morrissy AS, Meidinger J, Fish T, Green SC, Liu H, Li Y, Mungall AJ, Moore RA, Ma Y, Jones SJM, Marra MA, Vander Heiden MG, Taylor MD, Macdonald JM, Gershon TR. Cancer Res 77 3217-3230 (2017)
  4. Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism. Dunn J, Ferluga S, Sharma V, Futschik M, Hilton DA, Adams CL, Lasonder E, Hanemann CO. EBioMedicine 40 77-91 (2019)
  5. An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1-HK2+ Multiple Myeloma. Xu S, Zhou T, Doh HM, Trinh KR, Catapang A, Lee JT, Braas D, Bayley NA, Yamada RE, Vasuthasawat A, Sasine JP, Timmerman JM, Larson SM, Kim Y, MacLeod AR, Morrison SL, Herschman HR. Cancer Res 79 2748-2760 (2019)
  6. Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation. Nogueira V, Patra KC, Hay N. Elife 7 e32213 (2018)
  7. The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation. Nawaz MH, Ferreira JC, Nedyalkova L, Zhu H, Carrasco-López C, Kirmizialtin S, Rabeh WM. Biosci Rep 38 BSR20171666 (2018)
  8. A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis. Blaha CS, Ramakrishnan G, Jeon SM, Nogueira V, Rho H, Kang S, Bhaskar P, Terry AR, Aissa AF, Frolov MV, Patra KC, Brooks Robey R, Hay N. Nat Commun 13 899 (2022)
  9. Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis. Li WC, Huang CH, Hsieh YT, Chen TY, Cheng LH, Chen CY, Liu CJ, Chen HM, Huang CL, Lo JF, Chang KW. Front Oncol 10 176 (2020)
  10. A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers. Xu S, Catapang A, Braas D, Stiles L, Doh HM, Lee JT, Graeber TG, Damoiseaux R, Shirihai O, Herschman HR. Cancer Metab 6 7 (2018)
  11. MiR-302 Regulates Glycolysis to Control Cell-Cycle during Neural Tube Closure. Keuls RA, Kojima K, Lozzi B, Steele JW, Chen Q, Gross SS, Finnell RH, Parchem RJ. Int J Mol Sci 21 E7534 (2020)
  12. LigGrep: a tool for filtering docked poses to improve virtual-screening hit rates. Ha EJ, Lwin CT, Durrant JD. J Cheminform 12 69 (2020)
  13. Hexokinase 2 is targetable for HK1 negative, HK2 positive tumors from a wide variety of tissues of origin. Xu S, Catapang A, Doh HM, Bayley NA, Lee JT, Braas D, Graeber TG, Herschman HR. J Nucl Med jnumed.118.212365 (2018)
  14. Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes. Palombo R, Caporali S, Falconi M, Iacovelli F, Morozzo Della Rocca B, Lo Surdo A, Campione E, Candi E, Melino G, Bernardini S, Terrinoni A. Int J Mol Sci 20 E2689 (2019)
  15. A Novel Multiple-Read Screen for Metabolically Active Compounds Based on a Genetically Encoded FRET Sensor for ATP. Zhao Z, Rajagopalan R, Zweifach A. SLAS Discov 23 907-918 (2018)
  16. Glucose Metabolism Reprogramming in Bladder Cancer: Hexokinase 2 (HK2) as Prognostic Biomarker and Target for Bladder Cancer Therapy. Afonso J, Gonçalves C, Costa M, Ferreira D, Santos L, Longatto-Filho A, Baltazar F. Cancers (Basel) 15 982 (2023)
  17. Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities. Javadian P, Xu C, Sjoelund V, Borden LE, Garland J, Benbrook DM. Int J Mol Sci 23 7779 (2022)
  18. Identification of alkaline pH optimum of human glucokinase because of ATP-mediated bias correction in outcomes of enzyme assays. Šimčíková D, Heneberg P. Sci Rep 9 11422 (2019)
  19. Linker residues regulate the activity and stability of hexokinase 2, a promising anticancer target. Ferreira JC, Khrbtli AR, Shetler CL, Mansoor S, Ali L, Sensoy O, Rabeh WM. J Biol Chem 296 100071 (2021)
  20. Multi-Functional MPT Protein as a Therapeutic Agent against Mycobacterium tuberculosis. Kim JS, Cho E, Mun SJ, Kim S, Kim SY, Kim DG, Son W, Jeon HI, Kim HK, Jeong YJ, Jang S, Kim HS, Yang CS. Biomedicines 9 545 (2021)
  21. Predictors of functional benefit of hepatitis C therapy in a 'real-life' cohort. Steinebrunner N, Stein K, Sandig C, Bruckner T, Stremmel W, Pathil A. World J Gastroenterol 24 852-861 (2018)
  22. The Correlation of HK2 Gene Expression with the Occurrence, Immune Cell Infiltration, and Prognosis of Renal Cell Carcinoma. Liu C, Li H, Huang H, Zheng P, Li Z. Dis Markers 2022 1452861 (2022)
  23. Cytotoxic Activity of Amaryllidaceae Plants against Cancer Cells: Biotechnological, In Vitro, and In Silico Approaches. Trujillo L, Bedoya J, Cortés N, Osorio EH, Gallego JC, Leiva H, Castro D, Osorio E. Molecules 28 2601 (2023)
  24. Evaluation of biological properties of 3,3',4,4'-benzophenonetetracarboxylic dianhydride derivatives and their ability to inhibit hexokinase activity. Kochel K, Tomczyk MD, Simões RF, Frączek T, Soboń A, Oliveira PJ, Walczak KZ, Koceva-Chyła A. Bioorg Med Chem Lett 27 427-431 (2017)
  25. Protective Effect of Aquilaria crassna Leaf Extract against Benzo[a]pyrene-Induced Toxicity in Neuronal Cells and Caenorhabditis elegans: Possible Active Constituent Includes Clionasterol. Pattarachotanant N, Rangsinth P, Warayanon W, Leung GP, Chuchawankul S, Prasansuklab A, Tencomnao T. Nutrients 15 3985 (2023)
  26. Synthesis and Primary Activity Assay of Novel Benitrobenrazide and Benserazide Derivatives. Juszczak K, Szczepankiewicz W, Walczak K. Molecules 29 629 (2024)


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