Compounds for the modulation of beta-catenin expression

Abstract

The invention relates to oligomer compounds (oligomers), which target beta-catenin mRNA in a cell, leading to reduced expression of beta-catenin. Reduction of beta-catenin expression is beneficial for a range of medical disorders, such as hyperproliferative disorders, such as cancer. The invention provides therapeutic compositions comprising oligomers and methods for modulating the expression of beta-catenin using said oligomers, including methods of treatment.

1 . An oligomer consisting of 10 to 50 contiguous monomers wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group,
 wherein said oligomer comprises a first region of at least 10 contiguous monomers;   wherein at least one monomer of said first region is a nucleoside analogue;   wherein the sequence of said first region is at least 80% identical to the reverse complement of the best-aligned target region of a mammalian beta-catenin gene or a mammalian beta-catenin mRNA.   
     
     
         2 . The oligomer according to  claim 1 , wherein the sequence of the first region is at least 80% identical to a sequence of a region of at least 10 contiguous monomers present in SEQ ID NOs: 1-132, 174-192 or 193. 
     
     
         3 . The oligomer according to  claim 2 , wherein the sequence of the first region is at least 80% identical to a sequence of a region of at least 10 contiguous monomers present in SEQ ID NOs: 58, 103, 189 or 192. 
     
     
         4 . The oligomer according to  claim 2 , wherein the sequence of the first region is at least 80% identical to a sequence of a region of at least 10 contiguous monomers present in SEQ ID NO: 168 or 171. 
     
     
         5 . The oligomer according to  claim 1 , wherein the sequence of the first region comprises 0 to 2 mismatches when compared to the sequence of the best-aligned region of the reverse complement of a mammalian beta-catenin gene or a mammalian beta-catenin mRNA. 
     
     
         6 . The oligomer according to  claim 1 , wherein the first region of said oligomer consists of 10 to 18 contiguous monomers. 
     
     
         7 . The oligomer according to  claim 6 , wherein the first region of said oligomer consists of 16 contiguous monomers. 
     
     
         8 . The oligomer according to  claim 1 , wherein each nucleoside analogue is independently selected from the group consisting of an LNA monomer, a monomer containing a 2′-O-alkyl-ribose sugar, a monomer containing a 2′-O-methyl-ribose sugar, a monomer containing a 2′-amino-deoxyribose sugar, and a monomer containing a 2′fluoro-deoxyribose sugar. 
     
     
         9 . The oligomer according to  claim 8 , wherein the nucleoside analogue is an LNA monomer. 
     
     
         10 . The oligomer according to  claim 1 , wherein the oligomer is a gapmer, and wherein said gapmer comprises from the 5′ end to the 3′ end:
 (i) a region A consisting of 1-6 contiguous monomers, wherein at least one monomer is a nucleoside analogue,   (ii) a region B, the 5′ end of which is covalently linked to the 3′ end of region A and consisting of 5-12 contiguous monomers, wherein at least one monomer is a nucleoside; and   (iii) a region C, the 5′ end of which is covalently linked to the 3′ end of region B and consisting of 1-6 contiguous monomers, wherein at least one monomer is a nucleoside analogue.   
     
     
         11 . The oligomer according to  claim 10 , wherein the oligomer is a gapmer, and wherein said gapmer comprises from the 5′-end to the 3′-end:
 (i) a region A consisting of 2-5 contiguous monomers, wherein all monomers are nucleoside analogues,   (ii) a region B, the 5′ end of which is covalently linked to the 3′ end of region A and consisting of 6-10 contiguous monomers, wherein all monomers are nucleosides; and   (iii) a region C, the 5′ end of which is covalently linked to the 3′ end of region B and consisting of 2-5 contiguous monomers, wherein all monomers are nucleoside analogues.   
     
     
         12 . The oligomer according to  claim 10 , wherein all nucleoside analogues are LNA monomers. 
     
     
         13 . The oligomer according to  claim 1 , wherein said oligomer is selected from
 5′- Me C s   Me C s A s t s c s t s t s g s t s g s a s t s c s   Me C s A s T-3′ {SEQ ID NO: 168); and   5′-G s T s G s t s t s c s t s a s c s a s c s c s a s T s T s A-3′ (SEQ ID NO: 171),   
       wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript “s” denotes a phosphorothioate linkage, and MeC denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base. 
     
     
         14 . The oligomer according to  claim 1 , which inhibits the expression of a human beta-catenin gene or mRNA in a cell that expresses beta-catenin. 
     
     
         15 . A conjugate comprising an oligomer according to  claim 1  covalently attached to at least one moiety that is not a nucleic acid or a monomer. 
     
     
         16 . A pharmaceutical composition comprising the oligomer according to  claim 15 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant. 
     
     
         17 . A method of inhibiting the expression of beta-catenin in a cell, comprising contacting said cell with an effective amount of an oligomer consisting of 10 to 50 contiguous monomers wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group,
 wherein said oligomer comprises a first region of at least 10 contiguous monomers;   wherein at least one monomer of said first region is a nucleoside analogue;   wherein the sequence of said first region is at least 80% identical to the reverse complement of the best-aligned target region of a mammalian beta-catenin gene or a mammalian beta-catenin mRNA.   
     
     
         18 . A method of inhibiting the expression of beta-catenin in a cell, comprising contacting said cell with an effective amount of a conjugate according to  claim 15 . 
     
     
         19 . A method of inhibiting the expression of beta-catenin in a tissue of a mammal, comprising contacting said tissue with an effective amount of an oligomer consisting of 10 to 50 contiguous monomers wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group,
 wherein said oligomer comprises a first region of at least 10 contiguous monomers;   wherein at least one monomer of said first region is a nucleoside analogue;   wherein the sequence of said first region is at least 80% identical to the reverse complement of the best-aligned target region of a mammalian beta-catenin gene or a mammalian beta-catenin mRNA.   
     
     
         20 . A method of inhibiting the expression of beta-catenin in a tissue of a mammal comprising contacting said tissue with an effective amount of a conjugate according to  claim 15 . 
     
     
         21 . A method of treating cancer in a mammal, comprising administering to said mammal an effective amount of an oligomer consisting of 10 to 50 contiguous monomers wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group,
 wherein said oligomer comprises a first region of at least 10 contiguous monomers;   wherein at least one monomer of said first region is a nucleoside analogue;   wherein the sequence of said first region is at least 80% identical to the reverse complement of the best-aligned target region of a mammalian beta-catenin gene or a mammalian beta-catenin mRNA.   
     
     
         22 . The method of  claim 21 , wherein the cancer is selected from colorectal cancer, hepatocellular cancer, endometrial cancer, malignant melanoma, ovarian cancer, pancreatic cancer, pituitary cancer, esophageal cancer, lung cancer, breast cancer, kidney cancer, hematopoietic system cancer, cervical cancer, central nervous system cancer, bone cancer, biliary tract cancer and adrenal gland cancer. 
     
     
         23 . An activated oligomer consisting of 10 to 50 contiguous monomers wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group, wherein said activated oligomer comprises at least one functional group covalently attached thereto at one or more positions independently selected from the 5′-end, the 3′ end, the 2′-OH of a ribose sugar, and the base. 
     
     
         24 . An oligomer consisting of 10-25 monomers wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group,
 wherein said oligomer comprises a first region consisting of 10-24 monomers,   wherein the sequence of said first region is identically present in SEQ ID No: 189 or SEQ ID No: 192, or wherein the sequence of said first region comprises no more than one mismatch when compared to the best-aligned region of SEQ ID No: 189 or SEQ ID No: 192.   
     
     
         25 . A pharmaceutical composition comprising the conjugate according to  claim 15 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.