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Methods and Compositions for Treatment of Cancer (19) TZZ __T (11) EP 2 724 156 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/145 (2006.01) G01N 33/50 (2006.01) 16.08.2017 Bulletin 2017/33 C07C 309/51 (2006.01) C07C 311/08 (2006.01) C07C 311/14 (2006.01) C07C 335/20 (2006.01) (2006.01) (21) Application number: 12730343.6 C12Q 1/68 (22) Date of filing: 19.06.2012 (86) International application number: PCT/US2012/043074 (87) International publication number: WO 2013/003112 (03.01.2013 Gazette 2013/01) (54) METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASE VERFAHREN UND ZUSAMMENSETZUNGEN ZUR BEHANDLUNG VON KREBS UND AUTOIMMUNERKRANKUNGEN PROCÉDÉS ET COMPOSITIONS POUR LE TRAITEMENT DU CANCER ET D’UNE MALADIE AUTO-IMMUNE (84) Designated Contracting States: • T. ISHIDA ET AL: "DIDS, a chemical compound AL AT BE BG CH CY CZ DE DK EE ES FI FR GB that inhibits RAD51-mediated homologous GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO pairing and strand exchange", NUCLEIC ACIDS PL PT RO RS SE SI SK SM TR RESEARCH, vol. 37, no. 10, 30 March 2009 (2009-03-30), pages 3367-3376, XP055036178, (30) Priority: 27.06.2011 US 201161501522 P ISSN: 0305-1048, DOI: 10.1093/nar/gkp200 cited in the application (43) Date of publication of application: • MUNEER G HASHAM ET AL: "Widespread 30.04.2014 Bulletin 2014/18 genomicbreaks generatedby activation-induced cytidine deaminase are prevented by (73) Proprietor: The Jackson Laboratory homologous recombination", NATURE Bar Harbor, ME 04609 (US) IMMUNOLOGY, vol. 11, no. 9, 25 July 2010 (2010-07-25), pages820-826, XP055036263, ISSN: (72) Inventors: 1529-2908, DOI: 10.1038/ni.1909 • MILLS, Kevin David • HAITAO LI ET AL: Bar Harbor "2,3’,4,4’,5’-Pentamethoxy-trans-stilbene, a Maine 04609 (US) resveratrol derivative, inhibits colitis-associated • HASHAM, Muneer Gulamhusien colorectal carcinogenesis in mice", BRITISH Ellsworth JOURNAL OF PHARMACOLOGY, vol. 160, no. 6, Maine 04605 (US) 1 July 2010 (2010-07-01), pages 1352-1361, • MCPHEE, Caroline Gardner XP055036726, ISSN: 0007-1188, DOI: Seal Cove 10.1111/j.1476-5381.2010.00785.x Maine 04674 (US) • KIM Y H ET AL: "Piceatannol, a stilbene present in grapes, attenuates dextran sulfate (74) Representative: Kehoe, Laura Ellen et al sodium-induced colitis", INTERNATIONAL Keltie LLP IMMUNOPHARMACOLOGY, ELSEVIER, No.1 London Bridge AMSTERDAM, NL, vol. 8, no. 12, 10 December London SE1 9BA (GB) 2008 (2008-12-10), pages 1695-1702, XP025473993, ISSN: 1567-5769, DOI: (56) References cited: 10.1016/J.INTIMP.2008.08.003 [retrieved on WO-A1-03/039557 WO-A2-2004/021987 2008-09-04] 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 2 724 156 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 724 156 B1 • BADGER A M ET AL: "Idoxifene, a novel selective • HORVAT B ET AL: "Tumour cell proliferation is estrogen receptor modulator, is effective in a rat abolished by inhibitors of Na<+>H<+> and model of adjuvant-induced arthritis", JOURNAL HCO3<->Cl<-> exchange", EUROPEAN OF PHARMACOLOGY AND EXPERIMENTAL JOURNAL OF CANCER, PERGAMON PRESS, THERAPEUTICS, THE AMERICAN SOCIETY FOR OXFORD, GB, vol. 29, no. 1, 1 January 1993 PHARMACOLOGY AND EXPERIMENTAL (1993-01-01), pages132-137, XP026201861, ISSN: THERAPEUTICS, US, vol. 291, no. 3, 1 December 0959-8049, DOI: 10.1016/0959-8049(93)90591-3 1999 (1999-12-01), pages 1380-1386, [retrieved on 1993-01-01] XP002372594, ISSN: 0022-3565 • MONA LEUENBERGER ET AL: "AID protein • JIN-MING HWANG ET AL: "Reduction of anion expression in chronic lymphocytic exchanger 2 expression induces apoptosis of leukemia/small lymphocytic lymphoma is human hepatocellular carcinoma cells", associated with poor prognosis and complex MOLECULAR AND CELLULAR BIOCHEMISTRY, genetic alterations", MODERN PATHOLOGY, vol. KLUWER ACADEMIC PUBLISHERS, BO, vol. 327, 23, no. 2, 1 February 2010 (2010-02-01), pages no. 1-2, 18 February 2009 (2009-02-18), pages 177-186, XP055036781, ISSN: 0893-3952, DOI: 135-144, XP019684248, ISSN: 1573-4919 10.1038/modpathol.2009.156 • CHUNG-JUNG LIU ET AL: "Anion exchanger inhibitor DIDS induces human poorly-differentiated malignant hepatocellular carcinoma HA22T cell apoptosis", MOLECULAR AND CELLULAR BIOCHEMISTRY, KLUWER ACADEMIC PUBLISHERS, BO, vol. 308, no. 1-2, 16 October 2007 (2007-10-16), pages 117-125, XP019578300, ISSN: 1573-4919 2 EP 2 724 156 B1 Description Technical Field 5 [0001] The technology described herein relates to compounds for use in treating cancers and autoimmune diseases expressing activation-induced cytidine deaminase (AID) by inhibiting DNA double strand break repair mechanisms. Background 10 [0002] In 2010, there were an estimated 137,000 new cases of leukemia, lymphoma and multiple myeloma, and more than 54,000 deaths from these cancers in the United States alone. The current standard of care in leukemia/lymphoma treatment often involves intensive, long-term chemotherapy, which can be physically taxing for the patient. Common side effects of conventional chemotherapy include immune system disruption, myelosuppression, bone marrow destruc- tion, nausea, fatigue, liver toxicity, weight loss, hair loss, long-term cognitive impairment and therapy-related secondary 15 tumors. A major problem with standard chemotherapy is the damage done to otherwise healthy cells and tissues in the cancer patient. Current treatment often fails to achieve long-term remission, and patients who do survive routinely experience long-lasting chemotherapy-related health concerns that prevent them from ever being truly well. [0003] Selective targeting of the therapy specifically to the cancer cells could ameliorate most of these devastating side effects. Unfortunately, with few exceptions, selective targeting is technically difficult or impossible. Additional or 20 alternative approaches to selectively target cancer cells, while minimizing off-target side effects, are therefore desperately needed. [0004] T. ISHIDA ET AL: "DIDS, a chemical compound that inhibits RAD51-mediated homologous pairing and strand exchange", NUCLEIC ACIDS RESEARCH, vol. 37, no. 10, 30 March 2009, pages 3367-3376, describes DIDS as a RAD51 inhibitor. 25 [0005] MUNEER G HASHAM ET AL: "Widespread genomic breaks generated by activation-induced cytidine deami- nase are prevented by homologous recombination", NATURE IMMUNOLOGY vol. 11, no. 9, 25 July 2010, pages 820-826, describes that inhibition of XRCC2 using Xrcc2-specific shRNA in B cells expressing AID leads to compromised survival of the cells. [0006] HAITAO LI ET AL: "2,3’,4,4’,5’-Pentamethoxy-trans-stilbene, a resveratrol derivative, inhibits colitis-associated 30 colorectal carcinogenesis in mice", BRITISH JOURNAL OF PHARMACOLOGY, vol. 160, no. 6, 1 July 2010, pages 1352-1361, describes compounds suitable for treatment of colitis-associated colon cancer. [0007] KIM Y H ET AL: "Piceatannol, a stilbene present in grapes, attenuates dextran sulfate sodium-induced colitis", INTERNATIONAL IMMUNOPHARMACOLOGY,vol. 8, no. 12, 10 December 2008, pages 1695-1702, describes the use of picceatannol for the treatment of inflammatory bowel disease. 35 [0008] BADGER AM ET AL: "ldoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvant-induced arthritis", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 291, no. 3, 1 December 1999, pages 1380-1386 describes the therapeutic effect of idoxifene for treating rheumatoid arthritis. [0009] WO 03/039557 A1 describes compounds for treating autoimmune disease. [0010] WO 2004/021987 A2 describes compounds for treating rheumatoid arthritis. 40 [0011] JIN-MING HWANG ET AL: "Reduction of anion exchanger 2 expression induces apoptosis of human hepato- cellular carcinoma cells", MOLECULAR AND CELLULAR BIOCHEMISTRY,vol. 327, no. 1-2, 18 February 2009, pages 135-144 describes that DIDS inhibits cell proliferation and induces apoptosis in HA22T/VGH. [0012] CHUNG-JUNG LIU ET AL: "Anion exchanger inhibitor DIDS induces human poorly-differentiated malignant hepatocellular carcinoma HA22T cell apoptosis",MOLECULARAND CELLULAR BIOCHEMISTRY, vol. 308, no. 1-2, 16 45 October 2007, pages 117-125 describes that DIDS induces apoptosis in hepatocellular carcinoma HA22T cells. [0013] HORVAT B ET AL: "Tumour cell proliferation is abolished by inhibitors ofNa +H +and HC03 -Cl -exchange", EUROPEAN JOURNAL OF CANCER, vol. 29, no. 1, 1 January 1993, pages 132-137 describes that DIDS can have anti-proliferative effect or can potentiate the anti-proliferative effects of inhibitors of Na+/H+ exchangers. [0014] MONA LEUENBERGER ET AL: "AID protein expression in chronic lymphocytic leukemia/small lymphocytic 50 lymphoma is associated with poor prognosis and complex genetic alterations", MODERN PATHOLOGY,vol. 23, no. 2, 1 February 2010, pages 177-186, describes that AID expression is an indicator of an unfavourable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients. Summary 55 [0015] The present invention is defined in its broadest sense by the appended claims. [0016] The invention described herein is directed to an inhibitor of DNA double strand break repair for use in the treatment of cancer or an autoimmune disease in a subject having a detectable level of a DNA editing enzyme. As used 3 EP 2 724 156 B1 herein, "DNA editing enzyme" refers to an enzyme which normally catalyzes the mutation, exchange or excision of DNA segments, particularly enzymes which can generate or promote the generation of point mutations, DNA single strand breaks, DNA double-strand breaks or protein-DNA adducts. A DNA editing enzyme, as referred to herein, is not neces- sarily site-specific in its action. Similarly, it is not necessarily cell specific. Non-limiting examples of DNA editing enzyme s 5 include, but are not limited to Recombination Activating Gene 1 (RAG1; NCBI Gene ID: 5896, e.g.
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