E2F activity-inhibiting compound

Abstract

E2F-inhibiting compounds are represented by the general formula: R 1 -A-R 2 wherein A represents a peptide sequence comprising a partial amino acid sequence having at least 12 continuous residues in the sequence of the dimerization region or DNA binding region of the E2F family), which are useful as a therapeutic agent of diseases such as tumor and arteriosclerosis, for which abnormal cellular growth is responsible.

1 . (canceled)  
     
     
         2 . A compound represented by formula (I):  
         R 1 -A-R 2    (I)  
       wherein 
 R 1  represents substituted or unsubstituted alkanoyl substituted or unsubstituted aroyl. substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl or a hydrogen atom;  
 R 2  represents hydroxy substituted or unsubstituted alkoxy or substituted or unsubstituted amino; and  
 A is represented by formulae (Ia), Ib) or (Ic):  
                       (Ia, SEQ ID NO:25)                                       - (X 1 )n   - (X 2 )n   - (X 3 )n   - (Ala)n   - (X 5 )n   -                 (X 6 )n   - (X 7 )n   - (X 8 )n   - (X 9 )n   - Val   -             Gln   - Lys     Arg   - Arg   - Ile   -             Tyr   - Asp   - Ile   - Thr   - Asn   -             Val   - (Leu)n   - (Glu)n   - (Gly)n   - (Ile)   -             (X 26 )n   - (X 27 )n   - (X 28 )n   - (X 29 )n   -                                       
 (wherein “n's” independently represent 0 or 1; X 1 , X 8 , X 27  and X 28  independently represent Leu or Ile; X 2  represents Asn or Lys; X 3  represents Trp, Lys, Leu, Ala or Glu; X 5  represents Ala or Ser; X 6  represents Glu, Asp or Asn; X 7  represents Val, Thr or Arg; X 9  represents Lys, Asp, Ala or His; X 26  represents Gln, His, Gly, Asp or Asn; and X 29  represents Ala, Arg, Lys or Glu);  
                       (Ib, SEQ ID NO:26)                                       - (Y 1 )m   - (Y 2 )m   - (Y 3 )m   - (Gln)m   - (Y 5 )m   -                 (Y 6 )m   - (Asp)m   - (Gln)m   - (Y 9 )m   - (Asn)m   -             Ile   - Arg   - Arg   - Arg   - Val   -             Tyr   - Asp   - Ala   - Leu   - Asn   -             Val   - Leu   - Met   - Ala   - Y 25     -             (Asn)m   - (Y 27 )m   - (Ile)m   - (Ser)m   -                                       
 (wherein “m's” independently represent 0 or 1; Y 1  represents Asn, Thr, Ala or Tyr; y 2  represents Glu or Asp; Y 3  represents Ser or Asn; Y 5  represents Ala or Asn; Y 6  represents Tyr or Cys; Y 9  represents Lys or Glu; Y 25  represents Met or Ile; and y 27  represents Ile or Val);  
                       (Ic, SEQ ID NO:27)                                       - (Z 1 )p   - (Z 2 )p   - (Z 3 )p   - (Z 4 )p   - (Z 5 )p   -                 (Z 6 )p   - (Z 7 )p   - (Z 8 )p   - (Z 9 )p   - (Z 10 )p   -             (Z 11 )p   - (Z 12 )p   - (Z 13 )p   - (Z 14 )p   - (Z 15 )p   -             (Z 16 )p   - (Z 17 )p   - (Z 18 )p   - (Z 19 )p   - (Z 20 )p   -             (Z 21 )p   - (Z 22 )p   - (Z 23 )p   - (Z 24 )p   - (Z 25 )p   -             Arg   - Z 27     - Z 28     - Z 29     - Ser   -             Leu   - Z 32     - Leu   - Z 34     - Thr   -             Z 36     - Z 37     - Phe   - Z 39     - Z 40     -             Leu   -                                             
 (wherein “p's” independently represent 0 or 1; Z 1  represents Ala, Phe or Pro; Z 2  represents Arg, Lys, or Gln; Z 3 , Z 15  and Z 21  independently represent Gly or Pro; Z 4  represents Arg, Lys, Met or Pro; Z 5  represents Gly, Cys, Ala or Gln; Z 6  represents Ala, Arg or Glu; Z 7  represents Ala, Ile or Gln; Z 8  represents Ala, Gly or Arg, Z 9  represents Leu, Val or Pro; Z 10  represents Asp, Arg or Gln; Z 11  represents Gly, Ser, Ala or Pro; Z 12  represents Leu or Pro; Z 13  represents Asp, His or Pro; Z 14  represents Ser or Pro; Z 16  represents Gln or Lys; Z 17  represents Gly, Thr or Leu; Z 18  represents Gly, Pro or Val; Z 19  represents Gly or Lys; Z 20  represents Ala or Ser; Z 22  represents Gly or Ser; Z 23  represents Gly, Glu or Thr; Z 24  represents Arg, Lys, Ser or Pro; Z 25  represents Ser or Thr; Z 27  represents His or Tyr; Z 28  represents Asp or Glu; Z 29  and Z 36  independently represent Lys or Thr; Z 32  represents Gly or Asn; Z 34  represents Leu or Thr; Z 37  represents Arg or Lys; Z 39  represents Ile, Leu or Val; and Z 40  represents Glu, Gln, Ser or Tyr);  
 or a pharmaceutically acceptable salt thereof  
 with the proviso that A is not an intact peptide that which is a member of E2F family or DP family.  
 
     
     
         3 . A pharmaceutical composition comprising: 
 a pharmaceutically pure compound represented by formula (I):      R 1 -A-R 2    (I)    (wherein    R 1  represents substituted or unsubstituted alkanoyl, substituted or unsubstituted aroyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl or a hydrogen atom;    R 2  represents hydroxy, substituted or unsubstituted alkoxy, or substituted or unsubstituted amino; and    A represents a peptide sequence comprising a partial amino acid sequence having at least 12 continuous residues in the sequence of the dimerization region or DNA binding region of each E2F family)    or a pharmaceutically acceptable salt thereof; and    a pharmaceutically acceptable carrier.    
     
     
         4 . A compound according to  claim 2 , wherein A comprises SEQ ID NO:25, or a pharmaceutically acceptable salt thereof.  
     
     
         5 . A compound according to  claim 2 , wherein A consists of SEQ ID NO:26, or a pharmaceutically acceptable salt thereof.  
     
     
         6 . A compound according to  claim 2 , wherein A consists of SEQ ID NO:27, or a pharmaceutically acceptable salt thereof.  
     
     
         7 . A compound according to  claim 6 , wherein A consists of:  
       
         
           
                 
                 
                 
               
                     
                 
                   - Ile - Arg - Arg - Arg - Val - 
                   (SEQ ID NO: 23) 
                     
                 
                     
                 
                     Tyr - Asp - Ala - Leu - Asn - 
                 
                     
                 
                     Val - Leu - Met - Ala - Met - 
                 
                     
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         8 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to  claim 7 , and a pharmaceutically acceptable carrier.