Tumor Activated Prodrugs

Abstract

The instant invention provides compositions comprising a prodrug, the prodrug comprising a therapeutically active drug; and a peptide selected from the group consisting of the sequences: Ser-Ser-Lys-Tyr-Gln (SEQ ID NO:1); Gly-Lys-Ser-Gln-Tyr-Gln (SEQ ID NO:2); and Gly-Ser-Ala-Lys-Tyr-Gln (SEQ ID NO:3) wherein the peptide is linked to the therapeutically active drug to inhibit the therapeutic activity of the drug, and wherein the therapeutically active drug is cleaved from the peptide upon proteolysis by an enzyme having a proteolytic activity of prostate specific antigen (PSA). The invention further provides methods of making and using the claimed compositions.

1 . A composition comprising a prodrug, the prodrug comprising:
 a therapeutically active drug; and   a peptide selected from the group consisting of the sequences:   
     
       
         
               
               
               
             
                   
                 Ser-Ser-Lys-Tyr-Gln; 
                 (SEQ ID NO: 1) 
               
                   
                   
               
                   
                 Gly-Lys-Ser-Gln-Tyr-Gln; 
                 (SEQ ID NO: 2) 
               
                   
                 and 
               
                   
                   
               
                   
                 Gly-Ser-Ala-Lys-Tyr-Gln 
                 (SEQ ID NO: 3) 
               
           
              
              
              
              
              
              
             
          
         
       
       wherein the peptide is linked to the therapeutically active drug to inhibit the therapeutic activity of the drug, and wherein the therapeutically active drug is cleaved from the peptide upon proteolysis by an enzyme having a proteolytic activity of prostate specific antigen (PSA). 
     
   
   
       2 . The composition of  claim 1 , wherein the peptide is linked directly to the therapeutic drug. 
   
   
       3 . The composition of  claim 2 , wherein the peptide is linked directly to a primary amine group on the drug. 
   
   
       4 . The composition of  claim 1 , wherein the peptide is linked to the therapeutic drug via a linker. 
   
   
       5 . The composition of  claim 4 , wherein the linker is an amino acid sequence. 
   
   
       6 . The composition of  claim 5 , wherein the linker comprises a leucine residue. 
   
   
       7 . The composition of  claim 1 , wherein the therapeutically active drug inhibits a SERCA pump. 
   
   
       8 . The composition of  claim 7 , wherein the therapeutically active drug is selected from the group of primary amine containing thapsigargins or thapsigargin derivatives. 
   
   
       9 . The composition of  claim 8 , wherein the thapsigargin derivative is 8-O-(12-[L-leucinoylamino]dodecanoyl)-8-O-debutanoylthapsigargin (L12ADT). 
   
   
       10 . The composition of  claim 1 , wherein the therapeutically active drug intercalates into a polynucleotide. 
   
   
       11 . The composition of  claim 1 , wherein the therapeutic drug is a compound belonging to the group of thapsigargins which have been derivatized with a moiety containing a primary amino group and the linker is selected from the group consisting of unsubstituted or alkyl-, aryl-, halo-, alkoxy-, alkenyl-, amido-, or amino-substituted CO—(CH═CH) n1 —(CH 2 ) n2 —Ar—NH 2 , CO—(CH 2 ) n2 —(CH═CH) n1 —Ar—NH 2 , CO—(CH 2 ) n2 —(CH═CH) n1 —CO—NH—Ar—NH 2  and CO—(CH═CH) n1 —(CH 2 ) n2 —CO—NH—Ar—NH 2    wherein n1 and n2 are from 0 to 5, Ar is any substituted or unsubstituted aryl group, and attachment of NH 2  to Ar is in a ortho, meta or para position with respect to the remainder of the linker.   
   
   
       12 . The composition of  claim 1 , wherein the therapeutically active drug has an IC 50  toward ER Ca 2+ -ATPase of at most 500 nM. 
   
   
       13 . The composition of  claim 12 , wherein the therapeutically active drug has an IC 50  toward ER Ca 2+ -ATPase of at most 50 nM. 
   
   
       14 . The composition of  claim 1 , wherein the therapeutically active drug has an LC 50  toward PSA-producing tissue of at most 20 μM. 
   
   
       15 . The composition of  claim 14 , wherein the therapeutically active drug has an LC 50  toward PSA-producing tissue of less than or equal to 2.0 μM. 
   
   
       16 . The composition of  claim 1 , wherein cleavage of the peptide by the enzyme yields at least 5 picomoles of cleaved peptide per minute per 200 picomoles of enzyme. 
   
   
       17 . The composition of  claim 1 , wherein cleavage of the peptide in human serum yields at most 2.0 picomoles of cleaved peptide per minute. 
   
   
       18 . The composition of  claim 1 , further comprising an added substituent which renders the composition water soluble. 
   
   
       19 . The composition of  claim 18 , wherein the added substituent is a polysaccharide. 
   
   
       20 . The composition of  claim 19 , wherein the polysaccharide is selected from the group consisting of modified or unmodified dextran, cyclodextrin and starch. 
   
   
       21 . The composition of  claim 1  wherein the peptide is Ser-Ser-Lys-Tyr-Gln (SEQ ID NO:1). 
   
   
       22 . The composition of  claim 8  wherein the peptide is Ser-Ser-Lys-Tyr-Gln (SEQ ID NO:1). 
   
   
       23 . The composition of  claim 9  wherein the peptide is Ser-Ser-Lys-Tyr-Gln (SEQ ID NO:1). 
   
   
       24 - 37 . (canceled)