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Use of Inhibitors of the Enzyme TKTL1. Gebrauch Von Inhibitoren Des Enzyms TKTL1

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Use of Inhibitors of the Enzyme TKTL1. Gebrauch Von Inhibitoren Des Enzyms TKTL1 (19) TZZ ZZ_T (11) EP 2 256 500 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/51 (2006.01) 23.04.2014 Bulletin 2014/17 (21) Application number: 10009323.6 (22) Date of filing: 03.03.2006 (54) Use of inhibitors of the enzyme TKTL1. Gebrauch von Inhibitoren des Enzyms TKTL1. Utilisation d’inhibiteurs de l’enzyme TKTL1. (84) Designated Contracting States: • HEO HO JIN ET AL: "Protective effects of AT BE BG CH CY CZ DE DK EE ES FI FR GB GR quercetin and vitamin C against oxidative stress- HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI induced neurodegeneration", JOURNAL OF SK TR AGRICULTURAL AND FOOD CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 52, no. (30) Priority: 07.03.2005 EP 05004930 25, 15 December 2004 (2004-12-15), pages 17.06.2005 EP 05013170 7514-7517, XP002580650, ISSN: 0021-8561, DOI: 10.1021/JF049243R [retrieved on 2004-11-10] (43) Date of publication of application: • GEMA ALVAREZ ET AL: "Pyruvate Protection 01.12.2010 Bulletin 2010/48 Against beta-Amyloid- Induced Neuronal Death: Role of Mitochondrial Redox State", JOURNAL (62) Document number(s) of the earlier application(s) in OF NEUROSCIENCE RESEARCH, vol. 73, no. 2, accordance with Art. 76 EPC: 15 July 2003 (2003-07-15), pages 260-269, 06723195.1 / 1 856 537 XP55020916, • RAIS B ET AL: "Oxythiamine and (73) Proprietor: Coy, Dr., Johannes F. dehydroepiandrosterone induce a G1 phase 64853 Otzberg (DE) cycle arrest in Ehrlich’s tumor cells through inhibition of the pentose cycle", FEBS LETTERS, (72) Inventor: Coy, Dr., Johannes F. ELSEVIER, AMSTERDAM, NL, vol. 456, no. 1, 30 64853 Otzberg (DE) July 1999 (1999-07-30) , pages 113-118, XP004260049, ISSN: 0014-5793, DOI: (74) Representative: Rudolph, Ulrike 10.1016/S0014-5793(99)00924-2 Patentanwaltskanzlei Dr. U. Rudolph • Daniel A. Tennant ET AL: "Targeting metabolic In der Schanz 10 transformation for cancer therapy", Nature 69198 Schriesheim (DE) Reviews Cancer, vol. 10, no. 4, 1 April 2010 (2010-04-01), pages267-277, XP055059849, ISSN: (56) References cited: 1474-175X, DOI: 10.1038/nrc2817 US-A1- 2003 139 331 • DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, • CARL D BENNETT ET AL: "The Role of Dietary US 2008 WITTIG RAINER ET AL: ’The role of Fat in Protecting the Rat against Oxythiamine- glucose metabolism and glucose-associated produced Thiamine Deficiency", THE JOURNAL signalling in cancer.’ Database accession no. OF NUTRITION, vol. 99, no. 3, 1 November 1969 NLM19812737 & WITTIG RAINER ET AL: "The role (1969-11-01), pages 288-292, XP55020858, of glucose metabolism and glucose-associated signalling in cancer.", PERSPECTIVES IN MEDICINALCHEMISTRY 2008,vol. 1, 2008, pages 64-82, ISSN: 1177-391X Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 256 500 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 256 500 B1 • DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US 27 February 2006 LANGBEIN S ET AL: ’Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted.’ Database accession no. NLM16465194 & LANGBEIN S ET AL: "Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted.", BRITISH JOURNAL OF CANCER 27 FEB 2006, vol. 94, no. 4, 27 February 2006 (2006-02-27), pages 578-585, ISSN: 0007-0920 • DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US 01 February 2010 SUN WENYUE ET AL: ’TKTL1is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis through increased aerobic glycolysis and HIF1alpha stabilization.’ Database accession no. NLM20103683 & SUN WENYUE ET AL:"TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis through increased aerobic glycolysis and HIF1alpha stabilization.", CLINICAL CANCER RESEARCH : AN OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH 1 FEB 2010, vol. 16, no. 3, 1 February 2010 (2010-02-01), pages 857-866, ISSN: 1078-0432 2 1 EP 2 256 500 B1 2 Description some 3, the gene for TKTL2 is located on chromosome 4 and the gene for TKTL1 is located in band Xq28 on [0001] The invention relates to the use of a thiamine chromosome X. in humans. elected from the group consisting of oxythiamine, ben- [0004] One most important function of the enzyme fooxytiamine (=oxybenfotiamin), pyrithiamin and 2-meth- 5 TKTL1 in mammalian cells is its catalysator function dur- yithiamin for manufacturing a pharmaceutical composi- ing the fermentation of glucose to lactic acid in the pres- tion for the inhibition of the mammalian aerobic glucose ence of oxygen, i.e. under aerobic conditions. TKTL1 is fermentation metabolic pathway (mam-aGF) and for the tracer enzyme in the novel, first recently dicovered therapeutic treatment or controlling of diseases associ- so called mammalian aerobic glucose fermentation met- ated with an decreased or enhanced mammalian aerobic 10 abolic pathway or mammalian lactic acid fermentation glucose fermentation metabolic pathway (mam-aGF). process, respectively. In the following this newly discov- [0002] The invention is based on the novel scientific ered pathway is referred to as mammalian aerobic glu- discovery, that (1) a metabolism pathway which up to cose fermentation metabolic pathway or shortened to now has been known only from prokaryotic cells (for ex- mam-aGF, respectively. ample from lactobacillus), exists in mammalian organ- 15 [0005] Details of that mam-aGF are the following: isms - i.e. in mammalian cells - too, said metabolism path- way comprising the energy-yielding breaking down of A protein complex containing TKTL1 and glyceral- glucose to lactate , although sufficient free (molecular) dehyd-3-phosphate dehydrogenase (GAPD) allows oxygen is present and bioavailable i.e. aerobic conditions a nonoxidative glucose degradation. The electron exist, and that (2) the enzyme TKTL1 is the tracer enzyme 20 transfer does not involve mitochondria and allows a of said new glucose fermentation metabolism. mitochondria independent ATP production in TKTL1 [0003] Mammalian cells are able to break down glu- expressing cells. Application of anti-TKTL1 com- cose to lactic acid in the case of oxygen deficiency, finally pounds, or inhibitory thiamin-analogs, or paraben- leading to muscles ache. This anaerobic glucose degra- zoquinons (or benzoquinone-derivatives) can be ap- dation is performed via the Embden-Meyerhof-pathway. 25 plied for the inhibition of such a mitochondria inde- In the 1920s Otto Warburg discovered that also in the pendent ATP production (in particular for example presence of sufficient available amounts of oxygen mam- in tumors with a TKTL1 based sugar metabolism). malian cells are able to break down glucose to lactic acid, i.e. that mammalian cells are able to ferment glucose to [0006] Using the human TKTL1 protein the inventor of lactic acid even in the presence of sufficient amounts of 30 the present patent application confirmed the formation free bioavailable oxygen. He observed this anaerobic of glyceraldehyd-3-phosphate in an one-substrate reac- glucose to lactate degradation pathway in the presence tion utilizing X5P as sole carbon source. of oxygen in tumor tissues as well as in certain healthy [0007] The metabolism of X5P via TKTL1 result in the tissues like retina and testis. For historical reasons this formation of acetyl-CoA. The anaerobic glucose degra- glucose degradation to lactate even in the presence of 35 dation under aerobic conditions leads to lactate and the oxygen is named aerobic glycolysis or Warburg effect. building of the energy rich compound acetyl-CoA. The Since the start and end point (glucose and lactate) is the pyruvate dehydrogenase complex is then e.g. inhibited same as the glucose fermentation to lactate in the ab- by acetyl-CoA, and as a consequence, pyruvate is mainly sence of oxygen via the Embden-Meyerhof pathway, the reduced to lactate. lactate production has been interpreted as the result of 40 [0008] A schematic description of the complete mam- the Embden-Meyerhof pathway. However, in the course aGF are given in Fig. 13 and Fig. 14. of the experiments leading to the present invention it be- [0009] Details concerning the tracer enzyme TKTL1 of came obvious that it is the TKTL1 transketolase which that mam-aGF are the following: allows the glucose degradation or glucose fermentation, repectively, to lactate even in the presence of oxygen 45 During the experiments leading to the present inven- and that this glucose pathway is significantly different tion different TKTL1 isoforms were identified on pro- from the Embden-Meyerhof pathway. tein level using a novel monoclonal antibody (Linaris The TKTL1 transketolase gene has been discovered Biologische Produkte GmbH, Wertheim) specifically some years ago, namely 1996 by Coy et al. (Genomics detecting the TKTL1 protein. 32, 309-316). Due to a stop codon in a predicted coding 50 TKTL1 protein isoforms are part of a multi-protein exon, the TKTL1 transketolase gene has been annotated complex. Within this complex TKTL1 is also bound as a pseudogene in sequence data bases. Despite this, to transketolase unrelated proteins like glyceralde- in 2002 Coy demonstrated that the TKTL1 gene encodes hyd-3-phosphate dehydrogenase (GAPDH), DNa- an enzymatically active transketolase. The TKTL1 tran- seX (DNase1-like-1), Akt (= protein kinase B); his- sketolase is phylogentically cognate with the two other 55 tones, histon deacetylase, amyloid precursor protein known human transketolases TKT and TKTL2.
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