Methods and compounds for preventing and treating a tumour

Abstract

The invention relates to a method of preventing, inhibiting, arresting or reversing tumourigenesis in a cell as well as a method of inducing apoptosis in a tumour cell. The method includes increasing the amount and/or the activity of a DACT protein, or a functional fragment thereof, in the cell. Also provided is a pharmaceutical composition that comprises a compound of general formula (I) wherein A is CH or N, R 1 , R 4 and R 5 are independent from each other H, an aliphatic group, an alicyclic group, an aromatic group, an arylaliphatic group, and an arylalicyclic group comprising 0-3 heteroatoms. The heteroatoms may be N, O, S, or Si. R 4 and R 5 may optionally be linked so as to define an aliphatic hydrocarbyl bridge. R 2 is H or a halogen such as F, Cl, Br or I. R 3 is H, F, Cl or an aliphatic or arylaliphatic group that includes 1-8 main chain carbon atoms and 0-3 heteroatoms. The pharmaceutical composition also comprises a histone deacetylase inhibitor.

1 - 92 . (canceled) 
     
     
         93 . A method of preventing, inhibiting, arresting, or reversing tumourigenesis in a cell, the method comprising increasing at least one of the amount and the activity of a DACT (“dapper, antagonist of beta-catenin, homolog”) protein, or a functional fragment thereof, wherein the increase in the amount and the activity of the DACT protein, or the functional fragment thereof, is achieved by administering a compound that increases the expression and/or the activity of the DACT protein, or a functional fragment thereof, and wherein the compound is histone deacetylase inhibitor. 
     
     
         94 . The method of  claim 93 , wherein the cell is a rectal cell or a colon cell. 
     
     
         95 . The method of  claim 93 , wherein said tumourigenesis is carcinogenesis. 
     
     
         96 . The method of  claim 93 , wherein the cell is obtained from or is comprised in a host organism. 
     
     
         97 . The method of  claim 93 , wherein increasing at least one of the amount and the activity of a DACT protein, or a functional fragment thereof, further comprises reducing the amount of a dishevelled protein in the cell. 
     
     
         98 . A method of inducing apoptosis in a tumour cell, the method comprising increasing at least one of the amount and the activity of a DACT (“dapper, antagonist of beta-catenin, homolog”) protein, or a functional fragment thereof, in the cell, wherein the increase in the amount and the activity of the DACT protein, or the functional fragment thereof is achieved by administering a compound that increases the expression and/or the activity of the DACT protein, or a functional fragment thereof, and wherein the compound is histone deacetylase inhibitor. 
     
     
         99 . The method of  claim 98 , further comprising determining apoptosis in the tumour cell. 
     
     
         100 . The method of  claim 98 , wherein the tumour is one of cancer and ulcerative colitis. 
     
     
         101 . The method of  claim 100 , wherein the cancer is a one of a colorectal cancer, a melanoma, esophageal cancer, lung cancer, ovarian cancer, hepatocellular cancer, and endometrial cancer. 
     
     
         102 . The method of  claim 98 , wherein the cell is obtained from or is comprised in a host organism. 
     
     
         103 . The method of  claim 102 , wherein the host organism is one of a microorganism, a fish, an amphibian, a bird, and a mammal. 
     
     
         104 . The method of  claim 98 , wherein increasing at least one of the amount and the activity of a DACT protein, or a functional fragment thereof, further comprises reducing the amount of a dishevelled protein in the cell. 
     
     
         105 . The method of  claim 104 , wherein the dishevelled protein is one of Dvl1, Dvl2 and Dvl3. 
     
     
         106 . The method of  claim 93 , comprising contacting the cell with a predetermined quantity of a compound of the general formula (I) 
       
         
           
           
               
               
           
         
         wherein in formula (I) 
         A is CH or N, 
         R 1 , R 4  and R 5  are independently selected from the group consisting of H and aliphatic, alicyclic, aromatic, arylaliphatic, and arylalicyclic hydrocarbyl groups, comprising 0-3 heteroatoms selected from the group N, O, S, and Si,
 wherein R 4  and R 5  may optionally be linked so as to define an aliphatic hydrocarbyl bridge, 
 
         R 2  is selected from the group consisting of H and halogen, and 
         R 3  is H, or an aliphatic or arylaliphatic hydrocarbyl group comprising 1-8 main chain carbon atoms and 0-3 heteroatoms selected from the group N, O, S, Si, and halogen. 
       
     
     
         107 . The method of  claim 106 , comprising contacting the cell with a predetermined quantity of a combination of a compound of the general formula (I) and the histone deacetylase inhibitor. 
     
     
         108 . The method of  claim 107 , wherein the histone deacetylase inhibitor is a compound of one of the general formula (II) and the general formula (III), 
       
         
           
           
               
               
           
         
         wherein R 6  is one of H, an amino group, an ether group, an aliphatic group and an arylaliphatic group and 
         L is a bridge comprising an aliphatic or arylaliphatic group comprising 1-8 main chain carbon atoms and 0-3 heteroatoms selected from the group N, O and Si. 
       
     
     
         109 . A method of preventing or treating a tumour in a cell comprising administering to the cell a nucleic acid molecule comprising a histone deacetylase inhibitor that increases the absolute quantity of a DACT protein in a cell. 
     
     
         110 . A method of treating melanoma in a subject comprising administering to the subject a compound of the general formula (I). 
       
         
           
           
               
               
           
         
         wherein in formula (I) 
         A is CH or N, 
         R 1 , R 4  and R 5  are independently selected from the group consisting of H and aliphatic, alicyclic, aromatic, arylaliphatic, and arylalicyclic hydrocarbyl groups, comprising 0-3 heteroatoms selected from the group N, O, S, and Si,
 wherein R 4  and R 5  may optionally be linked so as to define an aliphatic hydrocarbyl bridge, 
 
         R 2  is selected from the group consisting of H and halogen, and 
         R 3  is H, or an aliphatic or arylaliphatic hydrocarbyl group comprising 1-8 main chain carbon atoms and 0-3 heteroatoms selected from the group N, O, S, Si, and halogen; 
       
       and a histone deacetylase inhibitor. 
     
     
         111 . A method of treating colorectal cancer in a subject comprising administering to the subject a compound of the general formula (I) 
       
         
           
           
               
               
           
         
         wherein in formula (I) 
         A is CH or N, 
         R 1 , R 4  and R 5  are independently selected from the group consisting of H and aliphatic, alicyclic, aromatic, arylaliphatic, and arylalicyclic hydrocarbyl groups, comprising 0-3 heteroatoms selected from the group N, O, S, and Si,
 wherein R 4  and R 5  may optionally be linked so as to define an aliphatic hydrocarbyl bridge, 
 
         R 2  is selected from the group consisting of H and halogen, and 
       
       R 3  is H, or an aliphatic or arylaliphatic hydrocarbyl group comprising 1-8 main chain carbon atoms and 0-3 heteroatoms selected from the group N, O, S, Si, and halogen;
 and a histone deacetylase inhibitor.