Small molecule modulators of epigenetic regulation and their therapeutic applications

Abstract

Disclosed are methods and compositions for modulating the function of transcription factors, especially transcription factors that recruit epigenetic regulators (histone modifying enzymes) to specific DNA promoters. The targeted transcription factors include but are not limited to the myocyte enhancing factor (MEF2), the forkhead/winged helix transcription factor FOXP3 and the transcription factor GATA3. Also disclosed are small molecule modulators of MEF2 and its associated factors that include but not limited to histone deacetylases (HDACs), p300/CBP and Cabin1 and the therapeutic applications thereof

1 - 36 . (canceled) 
     
     
         37 . A method of modulating one or more transcription factors and their functions, said method comprising contacting one or more transcription factors selected from the group consisting of myocyte enhancer factor-2 (MEF2)A, MEF2B, MEF2C, MEF2D, forkheadlwinged helix transcription factor 3 (FOXP3), and GATA-3, with one or more interfacial inhibitors having a formula of Ar 1 -L 1 -L 2 -L 3 -Ar 2  wherein:
 Ar 1  and Ar 2  are aromatic rings independently selected from the group consisting of benzene, naphthalene, pyridine, pyrimidine, pyrazine, quinolone, isoquinolone, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, thiazole, isoxazole, indole, benzimidazole, benzothiazole, and benzoxazole, provided that the aromatic ring may contain up to seven substituents selected from the group consisting of:
 hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, hydroxy, or halo; and wherein, substituents can also join together to form a ring of upto 12 atoms; and 
   L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O) 2 —; and   L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen, or sulfur atom, and further provided that these atoms can contain substituents selected from the group consisting of:
 alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxyl, alkoxy, aryloxy, oxa, keto, amido, sulfonamide, and fluoro. 
   
     
     
         38 . The method of  claim 37 , wherein the interfacial inhibitor is a compound having a formula of 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 -R 10  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, hydroxy, and halo; 
 L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O)2-; and 
 L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom, and further provided that these atoms can contain substituents selected from the group consisting of:
 alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxy, alkoxy, aryloxy, oxa, keto, amido, siilfonamido, and fluoro. 
 
 
     
     
         39 . The method of  claim 38 , wherein:
 L 2 -L 3  is L 2 -NHC(═O)— or L 2 -C(═O)NH— and L 1 -L 2  is —NHC(═O)-L 2  or —(O═)CHN-L 2 ; and   L 2  is a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom.   
     
     
         40 . The method of  claim 39 , wherein R 1 -R 10  are independently selected from the group consisting of hydrogen and halo, wherein at least one of R 1 -R 10  is a halo. 
     
     
         41 . The method of  claim 40 , wherein the halo is a bromine. 
     
     
         42 . The method of  claim 37 , wherein the interfacial inhibitor is a compound having a formula of 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 -R 5  are independently selected from the group consisting of hydrogen and halo, wherein at least one of R 1 -R 5  is a halo; 
 L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, acylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O)2-; and 
 L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom. 
 
     
     
         43 . The method of  claim 42 , wherein L 2 -L 3  is L 2 -NHC(═O)— or L 2 -C(═O)NH— and L 1 -L 2  is —NHC(═O)-L 2  or —(O═)CHN-L 2 . 
     
     
         44 . The method of  claim 43 , wherein the halo is a bromine. 
     
     
         45 . The method of  claim 37 , wherein one or more of the transcription factors are the same or different and one or more of the interfacial inhibitors are the same or different. 
     
     
         46 . The method of  claim 43 , wherein one or more of the transcription factors are the same or different and one or more of the interfacial inhibitors are the same or different. 
     
     
         47 . The method of  claim 37 , wherein the interfacial inhibitor is a compound having a formula selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         48 . A method of modulating one or more transcription factors and their functions in a subject suffering from a disease related to a transcription factor dysregulation; comprising:
 administering one or more interfacial inhibitors to the subject;   wherein the transcription factors are selected from the group consisting of MEF2A, MEF2B, MEF2C, MEF2D, FOX3P, GATA-3, and any combinations thereof; and   wherein the interfacial inhibitor is a compound having a formula of Ar 1 -L 1 -L 2 -L 3 -Ar 2  wherein:
 Ar 1  and Ar 2  are aromatic rings independently selected from the group consisting of benzene, naphthalene, pyridine, pyrimidine, pyrazine, quinolone, isoquinolone, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, thiazole, isoxazole, indole, benzimidazole, benzothiazole, and benzoxazole, provided that the aromatic ring may contain up to seven substituents selected from the group consisting of:
 hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, hydroxy, or halo; and wherein, substituents can also join together to form a ring of up to 12 atoms; and 
 
 L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O) 2 —; and 
 L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen, or sulfur atom, and further provided that these atoms can contain substituents selected from the group consisting of:
 alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxyl, alkoxy, aryloxy, oxa, keto, amido, sulfonamide, and fluoro. 
 
   
     
     
         49 . The method of  claim 48 , where the interfacial inhibitor is a compound having a formula of 
       
         
           
           
               
               
           
         
         wherein:
 R 1 -R 10  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, hydroxy, and halo; 
 L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O)2-; and 
 L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom, and further provided that these atoms can contain substituents selected from the group consisting of:
 alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxy, alkoxy, aryloxy, oxa, keto, amido, sulfonamido, and fluoro. 
 
 
       
     
     
         50 . The method of  claim 49 , wherein:
 L 2 -L 3  is L 2 -NHC(═O)— or L 2 -C(═O)NH— and L 1 -L 2  is —NHC(═O)-L 2  or —(O═)CHN-L 2 ; and   L 2  is a chain of up to 10 carbon atoms provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom.   
     
     
         51 . The method of  claim 50 , wherein R 1 -R 10  are independently selected from the group consisting of hydrogen and halo, wherein at least one of R 1 -R 10  is a halo. 
     
     
         52 . The method of  claim 51 , wherein the halo is a bromine. 
     
     
         53 . The method of  claim 49 , wherein the interfacial inhibitor is a compound having a formula of 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 -R 5  are independently selected from the group consisting of hydrogen and halo, wherein at least one of R 1 -R 5  is a halo; 
 L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —S(═O)—, and —S(═O)2-; and 
 L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom, and further provided that these atoms can contain substituents selected from the group consisting of:
 alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxy, alkoxy, aryloxy, oxa, keto, amido, sulfonamido, and fluoro. 
 
 
     
     
         54 . The method of  claim 54 , wherein:
 L 2 -L 3  is L 2 -NHC(═O)— or L 2 -C(═O)NH— and L 1 -L 2  is —NHC(═O)-L 2  or —(O═)CHN-L 2 ; and   L 2  is a chain of up to 10 carbon atoms provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom.   
     
     
         55 . The method of  claim 55 , wherein the halo is bromine. 
     
     
         56 . The method of  claim 48 , wherein one or more of the transcription factors are the same or different and one or more of the interfacial inhibitors are the same or different. 
     
     
         57 . The method of  claim 48 , wherein the transcription factor dysregulation results from a condition selected from the group comprising:
 genetic mutations of the transcription factors, genetic mutations of the transcription factor's binding partners, abnormal over-expression of the transcription factors, abnormal under-expression of the transcription factors, abnormal over-expression of the trancription factor's binding partners, and abnormal under-expression of the transcription factor's binding partners.   
     
     
         58 . The method of  claim 48 , wherein the disease is one selected from transplant rejection, inflammation, autoimmune diseases, neurodegenerative diseases, cancer, and cardiovascular disease. 
     
     
         59 . The method of  claim 48 , wherein a pharmaceutically effective amount of the one or more interfacial inhibitors is administered to the subject. 
     
     
         60 . The method of  claim 48 , wherein the interfacial inhibitor is a compound having a formula selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         61 . A method of modulating myocyte enhancer factor-2 (MEF2)-dependent transcription, said method comprising contacting one or more transcription factors selected from the group consisting of MEF2A, MEF2B, MEF2C, and MEF2D, with one or more interfacial inhibitors having a formula of Ar 1 -L 1 -L 2 -L 3 -Ar 2  wherein:
 Ar 1  and Ar 2  are aromatic rings independently selected from the group consisting of benzene, naphthalene, pyridine, pyrimidine, pyrazine, quinolone, isoquinolone, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, thiazole, isoxazole, indole, benzimidazole, benzothiazole, and benzoxazole, provided that the aromatic ring may contain up to seven substituents selected from the group consisting of:
 hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, hydroxy, or halo; and wherein, substituents can also join together to form a ring of upto 12 atoms; and 
   L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O) 2 —; and   L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen, or sulfur atom, and further provided that these atoms can contain substituents selected from the group consisting of:
 alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxyl, alkoxy, aryloxy, oxa, keto, amido, sulfonamide, and fluoro. 
   
     
     
         62 . The method of  claim 61 , wherein the interfacial inhibitors have a formula of 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 -R 10  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, hydroxy, and halo; 
 L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O)2-; and 
 L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom, and further provided that these atoms can contain substituents selected from the group consisting of:
 alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxy, alkoxy, aryloxy, oxa, keto, amido, sulfonamido, and fluoro. 
 
 
     
     
         63 . The method of  claim 63 , wherein:
 L 2 -L 3  is L 2 -NHC(═O)— or L 2 -C(═O)NH— and L 1 -L 2  is —NHC(═O)-L 2  or —(O═)CHN-L 2 ; and   L 2  is a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen, or a sulfur atom.   
     
     
         64 . The method of  claim 63 , wherein R 1 -R 10  are independently selected from the group consisting of hydrogen and halo, wherein at least one of R 1 -R 10  is a halo. 
     
     
         65 . The method of  claim 64 , wherein the halo is a bromine. 
     
     
         66 . The method of  claim 61 , wherein the interfacial inhibitor is a compound having a formula of 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 -R 5  are independently selected from the group consisting of hydrogen and halo, wherein at least one of R 1 -R 5  is a halo; 
 L 1  and L 3  are linking groups independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, —NHC(═O)—, —NR(C═O)—, —S(═O)—, and —S(═O)2-; and 
 L 2  is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, provided that up to three atoms can be replaced with an oxygen, nitrogen or sulfur atom. 
 
     
     
         67 . The method of  claim 66 , wherein L 2 -L 3  is L 2 -NHC(═O)— or L 2 -C(═O)NH— and L 1 -L 2  is —NHC(═O)-L 2  or —(O═)CHN-L 2 . 
     
     
         68 . The method of  claim 67 , wherein the halo is a bromine. 
     
     
         66 . The method of  claim 61 , wherein one or more of the transcription factors are the same or different and one or more of the interfacial inhibitors are the same or different. 
     
     
         67 . The method of  claim 61 , wherein the MEF2-dependent transcription occurs in tissue selected from the group including muscle, immune, and nervous system tissues.