An enolase inhibitor for the targeted treatment of ENO1-deleted cancers.
Animals
Antineoplastic Agents
/ therapeutic use
Biomarkers, Tumor
/ genetics
Cell Line, Tumor
DNA-Binding Proteins
/ genetics
Enzyme Inhibitors
/ therapeutic use
Female
Glioma
/ drug therapy
Glycolysis
/ drug effects
Humans
Macaca fascicularis
Male
Mice
Mice, SCID
Neoplasms
/ drug therapy
Phosphopyruvate Hydratase
/ antagonists & inhibitors
Precision Medicine
Sequence Deletion
Structure-Activity Relationship
Tumor Suppressor Proteins
/ genetics
Xenograft Model Antitumor Assays
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
16
01
2020
accepted:
15
10
2020
pubmed:
25
11
2020
medline:
6
1
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.
Identifiants
pubmed: 33230295
doi: 10.1038/s42255-020-00313-3
pii: 10.1038/s42255-020-00313-3
pmc: PMC7744354
mid: NIHMS1638168
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
DNA-Binding Proteins
0
Enzyme Inhibitors
0
Tumor Suppressor Proteins
0
ENO1 protein, human
EC 4.2.1.11
Phosphopyruvate Hydratase
EC 4.2.1.11
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1413-1426Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
ID : RP140612
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA225955
Pays : United States
Organisme : American Chemical Society (ACS)
ID : RSG-15-145-01-CDD
Pays : International
Organisme : NCI NIH HHS
ID : P50 CA127001
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
Fonvielle, M., Mariano, S. & Therisod, M. New inhibitors of rabbit muscle triose-phosphate isomerase. Bioorg. Med. Chem. Lett. 15, 2906–2909 (2005).
pubmed: 15911278
doi: 10.1016/j.bmcl.2005.03.061
Anderson, V. E., Weiss, P. M. & Cleland, W. W. Reaction intermediate analogues for enolase. Biochemistry 23, 2779–2786 (1984).
pubmed: 6380574
doi: 10.1021/bi00307a038
Muller, F. L. et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature 488, 337–343 (2012).
pubmed: 22895339
pmcid: 3712624
doi: 10.1038/nature11331
Leonard, P. G. et al. SF2312 is a natural phosphonate inhibitor of enolase. Nat. Chem. Biol. 12, 1053–1058 (2016).
pubmed: 27723749
pmcid: 5110371
doi: 10.1038/nchembio.2195
Boulard-Heitzmann, P. et al. Decreased red cell enolase activity in a 40-year-old woman with compensated haemolysis. Scand. J. Haematol. 33, 401–404 (1984).
pubmed: 6515323
doi: 10.1111/j.1600-0609.1984.tb00716.x
Stefanini, M. Chronic hemolytic anemia associated with erythrocyte enolase deficiency exacerbated by ingestion of nitrofurantoin. Am. J. Clin. Pathol. 58, 408–414 (1972).
pubmed: 4640298
doi: 10.1093/ajcp/58.5.408
Muller, F. et al. Enolase inhibitors and methods of treatment therewith. US Patent WO2016145113A1 (2016).
Krucinska, J. et al. Structural and functional studies of bacterial enolase, a potential target against gram-negative pathogens. Biochemistry 58, 1188–1197 (2019).
pubmed: 30714720
doi: 10.1021/acs.biochem.8b01298
Jiang H. et al. Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J. Natl. Cancer Inst. 99, 1410–1414 (2007).
Figueroa, J. et al. Exosomes from glioma-associated mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587. Cancer Res. 77, 5808–5819 (2017).
Yang, Y. et al. UOK 262 cell line, fumarate hydratase deficient (FH
Chan, D. A. et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl. Med. 3, 94ra70 (2011).
Pradere, U., Garnier-Amblard, E. C., Coats, S. J., Amblard, F. & Schinazi, R. F. Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem. Rev. 114, 9154–9218 (2014).
pubmed: 25144792
pmcid: 4173794
doi: 10.1021/cr5002035
Foster, K. J. et al. Blood intermediary metabolite and insulin concentrations after an overnight fast: reference ranges for adults, and interrelations. Clin. Chem. 24, 1568–1572 (1978).
Vasconcelos-dos-Santos, A. et al. Biosynthetic machinery involved in aberrant glycosylation: promising targets for developing of drugs against cancer. Front. Oncol. 5, 138 (2015).
Tarrado-Castellarnau, M., de Atauri, P. & Cascante, M. Oncogenic regulation of tumor metabolic reprogramming. Oncotarget 7, 62726–62753 (2016).
pubmed: 28040803
pmcid: 5308762
doi: 10.18632/oncotarget.10911
Pantelouris, E. M. Absence of thymus in a mouse mutant. Nature 217, 370–371 (1968).
pubmed: 5639157
doi: 10.1038/217370a0
Farquhar, D., Khan, S., Srivastva, D. N. & Saunders, P. P. Synthesis and antitumor evaluation of bis[(pivaloyloxy)methyl] 2′-deoxy-5-fluorouridine 5′-monophosphate (FdUMP): a strategy to introduce nucleotides into cells. J. Med. Chem. 37, 3902–3909 (1994).
pubmed: 7966151
doi: 10.1021/jm00049a009
Duysen, E. G. et al. Production of ES1 plasma carboxylesterase knockout mice for toxicity studies. Chem. Res. Toxicol. 24, 1891–1898 (2011).
pubmed: 21875074
pmcid: 3221923
doi: 10.1021/tx200237a
Rudakova, E. V., Boltneva, N. P. & Makhaeva, G. F. Comparative analysis of esterase activities of human, mouse, and rat blood. Bull. Exp. Biol. Med. 152, 73–75 (2011).
pubmed: 22803044
doi: 10.1007/s10517-011-1457-y
Bahar, F. G., Ohura, K., Ogihara, T. & Imai, T. Species difference of esterase expression and hydrolase activity in plasma. J. Pharm. Sci. 101, 3979–3988 (2012).
pubmed: 22833171
doi: 10.1002/jps.23258
Yan, V. C. & Muller, F. L. Advantages of the parent nucleoside GS-441524 over emdesivir for Covid-19 treatment. ACS Med. Chem. Lett. 11, 1361–1366 (2020).
pubmed: 32665809
pmcid: 7315846
doi: 10.1021/acsmedchemlett.0c00316
Humle, N. et al. Targeted vascular drug delivery in cerebral cancer. Curr. Pharm. Des. 22, 5487–5504 (2016).
pubmed: 27464719
doi: 10.2174/1381612822666160726113907
de Groot, J. F. & Yung, W. K. A. Bevacizumab and irinotecan in the treatment of recurrent malignant gliomas. Cancer J. 14, 279–285 (2008).
Nau, R., Sörgel, F. & Eiffert, H. Penetration of drugs through the blood-cerebrospinal fluid/blood–brain barrier for treatment of central nervous system infections. Clin. Microbiol. Rev. 23, 858–883 (2010).
pubmed: 20930076
pmcid: 2952976
doi: 10.1128/CMR.00007-10
Brunner, M. et al. Penetration of fosfomycin into the parenchyma of human brain: a case study in three patients. Br. J. Clin. Pharm. 54, 548–550 (2002).
Pfeifer, G., Frenkel, C. & Entzian, W. Pharmacokinetic aspects of cerebrospinal fluid penetration of fosfomycin. Int. J. Clin. Pharmacol. Res. 5, 171–174 (1985).
pubmed: 4018950
Naesens, L., Balzarini, J., Bischofberger, N. & De Clercq, E. Antiretroviral activity and pharmacokinetics in mice of oral bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine, the bis(pivaloyloxymethyl) ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine. Antimicrob. Agents Chemother. 40, 22–28 (1996).
pubmed: 8787873
pmcid: 163050
doi: 10.1128/AAC.40.1.22
Van Rompay, K. K. et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob. Agents Chemother. 48, 1469–1487 (2004).
Lockiec, F. Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention. Ann. Oncol. 17, iv33-6 (2006).
Benito, J. et al. Hypoxia-activated prodrug TH-302 targets hypoxic bone marrow niches in pre-clinical leukemia models. Clin. Cancer Res. 22, 1687–1698 (2016).
pubmed: 26603259
doi: 10.1158/1078-0432.CCR-14-3378
Beran, M., Andersson, B. S., Wang, Y., McCredie, K. B. & Farquhar, D. The effects of acetaldophosphamide, a novel stable aldophosphamide analogue, on normal human and leukemic progenitor cells in vitro: implications for use in bone marrow purging. Cancer Res. 48, 339–345 (1988).
Ludeman, S. M. The chemistry of the metabolites of cyclophosphamide. Curr. Pharm. Des. 5, 627–643 (1999).
pubmed: 10469895
Mazur, L., Opyodo-Chanek, M., Stojak, M. & Wojcieszek, K. Mafosfamide as a new anticancer agent: preclinical investigations and clinical trials. Anticancer Res. 32, 2783–2789 (2012).
pubmed: 22753738
Guise, C. P. et al. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chin. J. Cancer 33, 80–86 (2014).
pubmed: 23845143
pmcid: 3935009
doi: 10.5732/cjc.012.10285
Mazur, L., Opyodo-Chanek, M. & Stojak, M. Glufosfamide as a new oxazaphosphorine anticancer agent. Anticancer Drugs 22, 488–493 (2011).
pubmed: 21427562
doi: 10.1097/CAD.0b013e328345e1e0
Tobias, SandraC. & Borch, RichardF. Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs. J. Med. Chem. 44, 4475–4480 (2001).
pubmed: 11728193
doi: 10.1021/jm010337r
Wu, W., Sigmond, J., Peters, G. J. & Borch, R. F. Synthesis and biological activity of a gemcitabine phosphoramidate prodrug. J. Med. Chem. 50, 3743–3746 (2007).
pubmed: 17602464
pmcid: 2518329
doi: 10.1021/jm070269u
Sjövall, J., Bergdahl, S., Movin, G., Ogenstad, S. & Saarimäki, M. Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection. Antimicrob. Agents Chemother. 33, 1023–1031 (1989).
pubmed: 2528939
pmcid: 176056
doi: 10.1128/AAC.33.7.1023
Wager, T. T., Hou, X., Verhoest, P. R. & Villalobos, A. Central nervous system multiparameter optimization desirability: application in drug discovery. ACS Chem. Neurosci. 7, 3 (2016).
doi: 10.1021/acschemneuro.6b00029
Borch, R. F. et al. Synthesis and evaluation of nitroheterocyclic phosphoramidates as hypoxia-selective alkylating agents. J. Med. Chem. 43, 2258–2265 (2000).
pubmed: 10841804
doi: 10.1021/jm0001020
Yan, V. C. et al. Bioreducible phosphonoamidate pro-drug inhibitor of enolase: proof of concept study. ACS Med. Chem. Lett. 11, 1484–1489 (2020).
pubmed: 32676158
pmcid: 7357215
doi: 10.1021/acsmedchemlett.0c00203
Valk, P. E., Mathis, C. A., Prados, M. D., Gilbert, J. C. & Budinger, T. F. Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J. Nucl. Med. 33, 2133–2137 (1992).
pubmed: 1334136
Yan, V. C., Pham, C.-D. & Muller, F. L. Expedient method for direct mono-amidation of phosphonic and phosphoric acids. Preprint at ChemRxiv https://doi.org/10.26434/CHEMRXIV.12073131.V1 (2020).
Yan, V. C., Pham, C.-D., Arthur, K. & Muller, F. L. Aliphatic amines are viable pro-drug moieties in phosphonoamidate drugs. Preprint at bioRxiv https://doi.org/10.1101/2020.04.05.026583 (2020).
Powers, J. F. et al. A unique model for SDH-deficient GIST: an endocrine-related cancer. Endocr. Relat. Cancer 25, 943–954 (2018).
pubmed: 29967109
pmcid: 6097913
doi: 10.1530/ERC-18-0115
Maitituoheti, M. et al. Enhancer reprogramming confers dependence on glycolysis and IGF signaling in KMT2D mutant melanoma. Cell Rep. 33, 108293 (2020).
pubmed: 33086062
pmcid: 7649750
doi: 10.1016/j.celrep.2020.108293
Alam, H. et al. Super-enhancer impairment is a link between MLL4-inactivated lung tumors and their vulnerability to glycolysis pathway inhibition. Preprint at bioRxiv https://doi.org/10.1101/507202 (2018).
German, M. S. Glucose sensing in pancreatic islet beta cells: the key role of glucokinase and the glycolytic intermediates. Proc. Natl Acad. Sci. USA 90, 1781–1785 (1993).
Gaffney, DominiqueO. et al. Non-enzymatic lysine lactoylation of glycolytic enzymes. Cell Chem. Biol. 27, 206–213 (2020).
pubmed: 31767537
doi: 10.1016/j.chembiol.2019.11.005
Muller, F., Muller, F., Aquilanti, E. & DePinho, R. In vitro enzymatic activity assay for ENOLASE in mammalian cells in culture. Preprint at Protocol Exchange https://doi.org/10.1038/protex.2012.040 (2012).
Gillies, R. J., Didier, N. & Denton, M. Determination of cell number in monolayer cultures. Anal. Biochem. 159, 109–113 (1986).
pubmed: 3812988
doi: 10.1016/0003-2697(86)90314-3
Kueng, W., Silber, E. & Eppenberger, U. Quantification of cells cultured on 96-well plates. Anal. Biochem. 182, 16–19 (1989).
pubmed: 2604040
doi: 10.1016/0003-2697(89)90710-0
Bady, P. et al. DNA fingerprinting of glioma cell lines and considerations on similarity measurements. Neuro. Oncol. 14, 701–711 (2012).
pubmed: 22570425
pmcid: 3367844
doi: 10.1093/neuonc/nos072
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
pubmed: 18772396
pmcid: 2820389
doi: 10.1126/science.1164382
Nistér, M. et al. Evidence for progressional changes in the human malignant glioma line U-343 MGa: analysis of karyotype and expression of genes encoding the subunit chains of platelet-derived growth factor. Cancer Res. 47, 4953–4960 (1987).
pubmed: 3497714
Lal, S. et al. An implantable guide-screw system for brain tumor studies in small animals. J. Neurosurg. 92, 326–333 (2000).
pubmed: 10659021
doi: 10.3171/jns.2000.92.2.0326
Yuan, M., Breitkopf, S. B., Yang, X. & Asara, J. M. A positive/negative ion–switching, targeted mass spectrometry–based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat. Protoc. 7, 872–881 (2012).
pubmed: 22498707
pmcid: 3685491
doi: 10.1038/nprot.2012.024
Geoff, T. et al. Biological crystallography iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM. Acta Crystallogr. Sect. D. Biol. Crystallogr. 67, 271–281 (2011).
doi: 10.1107/S0907444910048675
Evans, P. R. & Murshudov, G. N. How good are my data and what is the resolution? Acta Crystallogr. Sect. D. Biol. Crystallogr. 69, 1204–1214 (2013).
doi: 10.1107/S0907444913000061
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. Sect. D. Biol. Crystallogr. 66, 486–501 (2010).
doi: 10.1107/S0907444910007493
Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. Sect. D. Biol. Crystallogr. 68, 352–367 (2012).
doi: 10.1107/S0907444912001308
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. Sect. D. Biol. Crystallogr. 66, 213–221 (2010).
doi: 10.1107/S0907444909052925
Lacy, S. A., M. J. Hitchcock, Lee, W. A., Telliert, P. & Cundy, K. C. Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cyno-molgus monkeys. Toxicol. Sci. 44, 97–106 (1998).
Van Rompay, K. K. A., Hamilton, M., Kearney, B. & Bischofberger, N. Pharmacokinetics of tenofovir in breast milk of lactating rhesus macaques. Antimicrob. Agents Chemother. 49, 2093–2094 (2005).
pubmed: 15855535
pmcid: 1087653
doi: 10.1128/AAC.49.5.2093-2094.2005
Van Rompay, K. K. A. et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob. Agents Chemother. 48, 2346 (2004).
Naesens, L. et al. Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice. Antimicrob. Agents Chemother. 42, 1568–1573 (1998).
pubmed: 9660984
pmcid: 105646
doi: 10.1128/AAC.42.7.1568
Duwal, S., Schütte, C. & von Kleist, M. Pharmacokinetics and pharmacodynamics of the reverse transcriptase inhibitor tenofovir and prophylactic efficacy against HIV-1 infection. PLoS ONE 7, e40382 (2012).
pubmed: 22808148
pmcid: 3394807
doi: 10.1371/journal.pone.0040382
Deeks, S. G. et al. Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(phosphonomethoxy)propyl]adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults. Antimicrob. Agents Chemother. 42, 2380–2384 (1998).
Cundy, K. C. et al. Pharmacokinetics and bioavailability of the anti-human immunodeficiency virus nucleotide analog 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in dogs. Antimicrob. Agents Chemother. 42, 687–690 (1998).
pubmed: 9517952
pmcid: 105518
doi: 10.1128/AAC.42.3.687
Zykov, I. N. et al. Pharmacokinetics and pharmacodynamics of fosfomycin and its activity against extended-spectrum-lactamase-, plasmid-mediated AmpC-, and carbapenemase-producing Escherichia coli in a murine urinary tract infection model. Antimicrob. Agents Chemother. 62, e02560-17 (2018).
Pérez, D. S., Tapia, M. O. & Soraci, A. L. Fosfomycin: uses and potentialities in veterinary medicine. Open Vet. J. 4, 26–43 (2014).
pubmed: 26623336
pmcid: 4629597
Kirby, W. M. M. Pharmacokinetics of fosfomycin. Chemotherapy 23, 141–151 (1977).
pubmed: 832510
doi: 10.1159/000222040
Murakawa, T., Sakamoto, H., Fukada, S., Konishi, T. & Nishida, M. Pharmacokinetics of fosmidomycin, a new phosphonic acid antibiotic. Antimicrob. Agents Chemother. 21, 224–230 (1982).
pubmed: 7073262
pmcid: 181863
doi: 10.1128/AAC.21.2.224