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LNA oligonucleotides and the treatment of cancer

An oligonucleotide and nucleotide technology, applied in the field of cancer treatment, can solve problems such as the good performance of LNA oligonucleotides that have not been described

Inactive Publication Date: 2007-10-31
SANTARIS PHARMA AS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the surprisingly good properties of the LNA oligonucleotides disclosed herein have not been described in the prior art

Method used

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  • LNA oligonucleotides and the treatment of cancer
  • LNA oligonucleotides and the treatment of cancer
  • LNA oligonucleotides and the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0106] Preparation of LNA oligonucleotides

[0107] LNA nucleotide analog building blocks (β-D-oxy-LNA, β-D-sulfo-LNA, β-D-amino-LNA and α-L-oxy-LNA can be prepared following published methods and literature cited therein. LNA), see, for example,

[0108] WO 03 / 095467 A1; D.S.Pedersen, C.Rosenbohm, T.Koch (2002) Preparation of LNA Phosphoramidites, Synthesis 6, 802-808; .Verbeure, G.Gaubert, P.Herdewijn, J.Wengel (2002) α-L-ribo-configured Locked Nucleic Acid (α-L-LNA): Synthesis and Properties, J.Am.Chem.Soc., 124, 1998 , 63, 6078-6079; C.Rosenbohm, S.M.Christensen, M.D.Srensen, D.S.Pedersen, L, E.Larsen, J.Wengel.T.Koch (2003) Synthesis of 2′-amino-LNA; a new strategy, Org. Biomol. Chem. 1, 655-663; and WO 2004 / 069991 A2.

[0109] LNA oligonucleotides can be prepared as described in the Examples and WO 99 / 14226, WO 00 / 56746, WO 00 / 56748, WO 00 / 66604, WO 00 / 125248, WO 02 / 28875, WO 2002 / 094250 and WO03 / 006475 acid. Thus, LNA oligonucleotides can be prepared using nuclei...

Embodiment 1

[0258] Embodiment 1: monomer synthesis

[0259] LNA monomer building blocks and derivatives thereof were prepared according to published methods and literature cited therein, see:

[0260] WO 03 / 095467 A1

[0261] D. S. Pedersen, C. Rosenbohm, T. Koch (2002) Preparation of LNA Phosphoramidites, Synthesis 6, 802-808.

[0262] M.D.Srensen, L.Kvrn, T.Bryld, A.E.Hkansson, B.Verbeure, G.Gaubert, P.Herdewijn, J.Wengel (2002) α-L-ribo-configured Locked Nucleic Acid (α- L-LNA): Synthesis and Properties, J. Am. Chem. Soc., 124, 2164-2176.

[0263] S.K.Singh, R.Kumar, J.Wengel(1998) Synthesis of Novel Bicyclo[2.2.1]Ribonucleosides: 2′-Amino-and 2′-Thio-LNA Monomeric Nucleosides, J.Org.Chem.1998, 63, 6078 -6079.

[0264] C. Rosenbohm, S.M.Christensen, M.D.S.rensen, D.S.Pedersen, L.E.Larsen, J.Wengel, T.Koch (2003) Synthesis of 2'-amino-LNA: a new strategy, Org.Biomol.Chem.1, 655- 663. D.S.Pedersen, T.Koch (2003) Analogues of LNA (Locked Nucleic Acid). Synthesis of the 2′-Thio-LN...

Embodiment 2

[0265] Example 2: Oligonucleotide Synthesis

[0266] Oligonucleotides were synthesized on an Expedite 8900 / MOSS synthesizer (Multiple Oligonucleotide Synthesis System) using the phosphoramidite method on a 1 μmol or 15 μmol scale. For larger-scale syntheses, use the kta Oligo Pilot. At the end of the synthesis (with DMT), the oligonucleotides were cleaved from the solid support using ammonia for 1-2 hours at room temperature and further deprotected at 65°C for 4 hours. The oligonucleotides were purified by reverse phase HPLC (RP-HPLC). After removing the DMT group, the oligonucleotides were characterized by AE-HPLC, RP-HPLC and CGE, and the molecular weight was further confirmed by ESI-MS. See below for more details.

[0267] Preparation of LNA-solid support:

[0268] Preparation of LNA succinyl half ester

[0269] 5'-O-DMT-3'-hydroxy-LNA monomer (500 mg), succinic anhydride (1.2 equiv) and DMAP (1.2 equiv) were dissolved in DCM (35 ml). The reaction was stirr...

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Abstract

The present disclosure concerns LNA oligonucleotides having a (sub)sequence of the general formula 5'- ( Me Cx )(Tx,) Me CXAs Astscscsastsgsgs MeCXAX (G x) (c)-3',and preferably of the general formula 5'- Me C XTX), MeCXAsastscscsastsgsgs Me CxAx G x c-3', wherein capital letters designate a n LNA nucleotide analogue selected from .beta. -D-oxy-LNA, .beta. -D-thio-LNA, .beta.-D-amino-LNA and a-L-oxy-LNA, small letters designate a deoxynucleotid e, and underline designates either an LNA nucleotide analogue as defined above or a deoxynucleotide. Such LNA oligonucleotides exhibit surprisingly good properties with respect to inhibition of the expression of Survivin by means of an anti-sense mechanism, and thereby lead to reduction or inhibition of tumour development in vivo. The LNA oligonucleotides are superior to other L NA oligonucletides targeting Surviving mRNA measured by functional read outs such as apoptosis induction and proliferation inhibition, and is potent in down- regulating Survivin mRNA and protein in transfected cancer cell lines, and induce apoptosis in combination with Taxol superior compared to other LNA oligonucleotides.

Description

field of invention [0001] The present invention provides pharmaceutical compositions for treating cancer. The composition comprises specific LNA oligonucleotides which have superior properties in inhibiting the expression of survivin. The invention also provides methods and various kits for treating cancer. Background of the invention [0002] Survivin is one of the most attractive new cancer targets. High levels of Survivin were detected in nearly all tumor types, underscoring the protein's clinical role in cancer. Elevated expression of survivin in tumors is often associated with poor prognosis, increased cancer recurrence and resistance to treatments (radiation and chemotherapy). The fact that survivin is not expressed in normal adult tissues (with a few exceptions) makes survivin a key oncogene. [0003] Inhibitor of apoptosis protein (IAP) Survival proteins are involved in 2 key biological events: (i) control of cell proliferation (mitosis), and (ii) regulation of p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/11A61P35/00A61K31/7088
Inventor L·S·卡耶洛夫M·阿斯克伦德M·韦斯特加德C·罗森鲍姆M·韦森巴赫B·汉森
Owner SANTARIS PHARMA AS
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