Compositions and methods for treatment of leukemia

Abstract

The invention relates generally to effective treatment leukemia. In particular, the present invention provides compositions and methods to inhibit the interaction of menin with MLL and MLL-fusion oncoproteins, and well as systems and methods to screen for such compositions.

What is claimed is: 
     
         1 . A pharmaceutical preparation comprising a compound having the structure or pharmaceutically acceptable salts of thereof: 
       
         
           
           
               
               
           
         
       
       wherein R1, R2, R3, R4, R5, R6, R7, and R8 independently comprise: H, substituted or non-substituted alkyl, substituted or non-substituted alkoxy, a halogen (e.g. F, Cl, Br, I, and At), a ketone, a carbocyclic ring, an aromatic ring, a heterocyclic aromatic ring comprising carbon and one or more nitrogen, oxygen and/or sulfur members which may be non-substituted or substituted with substituted or non-substituted alkyl, aryl, halogen, hydrogen bond donor or acceptor, a heterocyclic non-aromatic ring comprising carbon and one or more nitrogen, oxygen and/or sulfur members which may be non-substituted or substituted with alkyl, aryl, halogen, hydrogen bond donor or acceptor, carbocyclic aromatic or non-aromatic ring fused or attached to the thienopyrimidine ring system non-substituted or substituted with alkyl, aryl, halogen, hydrogen bond donor or acceptor, carbocyclic or heterocyclic aromatic ring comprising carbon atoms and one or more nitrogen, oxygen and/or sulfur members fused to another aromatic ring, or a hydrogen bond donor or a hydrogen bond acceptor; Z is S or O or NH or CH—CH; W is present or absent and is NH or NH—(CH 2 ) n  (n=0-10), or (CH 2 ) n  (n=0-10) or O or O—(CH 2 ) n  (n=0-10); X and Y are each independently N or C; and m is 0-3. 
     
     
         2 . The pharmaceutical preparation of  claim 1 , wherein said structure is Compound 1. 
     
     
         3 . The pharmaceutical preparation of  claim 1 , wherein said structure is Compound 4. 
     
     
         4 . The pharmaceutical preparation of  claim 1 , wherein said structure is selected from the group consisting of Compounds 2-3, 5-31, and 60-83. 
     
     
         5 . The pharmaceutical preparation of  claim 1 , wherein said structure is any structural analogue of compositions 1-31 and 60-83. 
     
     
         6 . A pharmaceutical preparation comprising a compound having the structure or pharmaceutically acceptable salts of thereof: 
       
         
           
           
               
               
           
         
       
       wherein R1, R2, R3, and R4 each independently comprise: H, substituted or non-substituted alkyl, substituted or non-substituted alkoxy, a halogen, a ketone, a carbocyclic ring, an aromatic ring, a heterocyclic aromatic ring comprising carbon and one or more nitrogen, oxygen and/or sulfur members which may be non-substituted or substituted with alkyl, aryl, halogen, hydrogen bond donor or acceptor, a heterocyclic non-aromatic ring comprising carbon and one or more nitrogen, oxygen and/or sulfur members which may be non-substituted or substituted with alkyl, aryl, halogen, hydrogen bond donor or acceptor, carbocyclic aromatic or non-aromatic ring fused to the benzodiazepine ring system non-substituted or substituted with alkyl, aryl, halogen, hydrogen bond donor or acceptor, carbocyclic or heterocyclic aromatic ring comprising carbon atoms and one or more nitrogen, oxygen and/or sulfur members fused to another aromatic ring, or a hydrogen bond donor or a hydrogen bond acceptor. 
     
     
         7 . The pharmaceutical preparation of  claim 6 , wherein said structure is Compound 32. 
     
     
         8 . The pharmaceutical preparation of  claim 6 , wherein said structure is Compound 33. 
     
     
         9 . The pharmaceutical preparation of  claim 6 , wherein said structure is Compound 34. 
     
     
         10 . The pharmaceutical preparation of  claim 6 , wherein said structure is selected from the group consisting of Compounds 35-41. 
     
     
         11 . The pharmaceutical preparation of  claim 6 , wherein said structure is selected from the group consisting of Compounds 84-86. 
     
     
         12 . The pharmaceutical preparation of  claim 6 , wherein said structure is any structural analogue of compositions 35-41 and 84-86. 
     
     
         13 . A pharmaceutical preparation comprising a compound having the structure of Compound 42-59. 
     
     
         14 . A method, comprising: administering a composition of  claim 1  to a subject. 
     
     
         15 . The method of  claim 14 , wherein said subject is a human. 
     
     
         16 . The method of  claim 14 , wherein said subject is non-human animal. 
     
     
         17 . The method of  claim 1 , wherein said human is suffering from leukemia. 
     
     
         18 . The method of  claim 17 , wherein said leukemia comprises AML or ALL. 
     
     
         19 . A method, comprising: administering a composition of  claim 6  to a subject. 
     
     
         20 . The method of  claim 19 , wherein said subject is a human. 
     
     
         21 . The method of  claim 19 , wherein said subject is non-human animal. 
     
     
         22 . The method of  claim 20 , wherein said human is suffering from leukemia. 
     
     
         23 . The method of  claim 22 , wherein said leukemia comprises AML or ALL. 
     
     
         24 . A method of inhibiting the interaction of MLL and menin comprising:
 a) providing:
 i) a sample comprising MLL or MLL fusion protein and menin; and 
 ii) a composition configured to inhibit the interaction of MLL or MLL fusion protein and menin, wherein said composition is a comprises a thienopyrimidine class compound or a benzodiazepine class compound; 
   b) administering said composition to said sample; and   c) inhibiting the interaction between said MLL and said menin, or said MLL fusion proteins and said menin.   
     
     
         25 . The method of  claim 24 , wherein said composition comprises a compound selected from the group consisting of Compounds 1-86.