Use of caseinolytic protease p function as a biomarker of drug response to imipridone-like agents

Abstract

Use of caseinolytic protease P (ClpP) function and/or concentration as a biomarker for predicting the response of a neoplastic disease, preferably cancer or another disease where enhancing ClpP activity may provide a therapeutic benefit, to a compound of Formula I. In other aspects it relates to methods and kits, as well as methods of treatment involving the use of the biomarker.

We claim: 
     
         1 . A compound of the general Formula I:
   Z1-Q  Formula I
   or a pharmaceutically acceptable salt thereof, wherein:
 Z1 is: 
   
       
         
           
           
               
               
           
         
         
           Z2 is: 
         
       
       
         
           
           
               
               
           
         
         Q is independently selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         Ar1 and Ar2 are independently selected from aryl, heteroaryl, thiophenyl and phenyl; 
         Ar1 may be optionally substituted with from 1 to 3 J groups; 
         Ar2 is substituted with from 1 to 3 JJ groups; 
         J is independently selected from halogen, —CN, (C1-C6) optionally substituted alkyl, (C3-C9) optionally substituted cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl, (C1-C6)haloalkyl, —CF 3 , —NH 2 , —NO 2 , —SH, —SR15, —OH, (C1-C6) optionally substituted alkoxy, —NR17R18, substituted (C3-C9)cycloalkyl(C1-C6)alkyl, (C3-C9)cycloalkyl(C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenyl(C1-C6)alkyl, aryl, heteroaryl, heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —C(O)OH, —C(O)OR15, —OC(O)OR15, (C2-C6)alkynyl, (C2-C8)alkenyl, (C1-C6)haloalkyoxy, —S(O) 2 OR15, —SO 2 NR17R18, —S(O) 2 R15, —NR15S(O) 2 R16, —C(O)NR17R18, —C(O)R15, and —NR15C(O)R16; 
         JJ is independently selected from halogen, —CN, (C1-C6)haloalkyl, (C1-C6) optionally substituted alkyl, —CF 3 , —NH 2 , —NO 2 , —SH, —SR15, —OH, (C1-C6) optionally substituted alkoxy, —NR17R18, aryl, heteroaryl, —C(O)OH, —C(O)OR15, —OC(O)OR15, (C2-C6)alkynyl, (C2-C8)alkenyl, (C1-C6)haloalkyoxy, —S(O) 2 OR15, —SO 2 NR17R18, —S(O) 2 R15, —NR15S(O) 2 R16, —C(O)NR17R18, —C(O)R15, and —NR15C(O)R16; 
         R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from hydrogen, halogen, —OH and (C1-C3) optionally substituted alkyl; 
         R5 and R6 may be taken together to form ═O; 
         R7 and R8 may be taken together to form ═O; 
         R14 is independently selected from hydrogen, halogen, (C1-C6) optionally substituted alkyl, (C3-C6)cycloalkyl, (C1-C6)haloalkyl, (C2-C6) optionally substituted alkenyl, (C2-C6) optionally substituted alkynyl, —CN, —S(O) 2 R15, —NR17R18, —S(O) 2 R15, —C(NH)NH 2 , —C(O)R15, and —C(O)OR15; 
         R15, R16, R17, R18 and R29 are independently selected from hydrogen and (C1-C6) optionally substituted alkyl; 
         R17 and R18 together with nitrogen to which they are attached may form a ring of 3 to 6 atoms; 
         W4 is independently selected from the group consisting of ═C(R14)- and nitrogen; 
         A is independently selected from the group consisting of SS and 
       
       
         
           
           
               
               
           
         
         G is independently selected from the group consisting of SS and 
       
       
         
           
           
               
               
           
         
         M is independently selected from the group consisting of SS and 
       
       
         
           
           
               
               
           
         
         E is independently selected from the group consisting of a single bond, SS, and 
       
       
         
           
           
               
               
           
         
         SS is independently selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R20, R21, R26 and R27 are each independently selected from the group consisting of hydrogen, halogen and (C1-C6) optionally substituted alkyl; 
         R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, halogen, —CN, (C1-C6) optionally substituted alkyl, (C3-C9) optionally substituted cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl, (C1-C6)haloalkyl, —NH 2 , —NO 2 , —SH, —SR15, —OH, (C1-C6) optionally substituted alkoxy, —NR17R18, substituted (C3-C9)cycloalkyl(C1-C6)alkyl, (C3-C9)cycloalkyl(C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenyl(C1-C6)alkyl, aryl, heteroaryl, —C(O)OH, —C(O)OR15, —OC(O)OR15, (C2-C6)alkynyl, (C2-C8)alkenyl, (C1-C6)haloalkyoxy, —S(O) 2 OR15, —SO 2 NR17R18, —S(O) 2 R15, —NR15S(O) 2 R16, —C(O)NR17R18, —C(O)R15, and —NR15C(O)R16; 
         R22 and R23 together with the carbon to which they are attached may form a nonaromatic ring having 3 to 6 carbon atoms; 
         R22 and R23 together with the carbon to which they are attached may form a nonaromatic ring having 1-2 oxygen atoms; 
         R24 and R25 together with the carbon to which they are attached may form a nonaromatic ring having 1-2 oxygen atoms; 
         R24 and R25 together with the carbon to which they are attached may form a nonaromatic ring having 3 to 6 carbon atoms; 
         R30 and R31 are each is independently selected from the group consisting of hydrogen and (C1-C6) optionally substituted alkyl. 
       
     
     
         2 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 Q is Q3. 
 
     
     
         3 . The compound of  claim 2  or pharmaceutically acceptable salt thereof, wherein:
 R1, R2, R3 and R4 are each hydrogen; 
 Ar1 is phenyl; 
 Ar2 is phenyl; 
 R5, R6, R7 and R8 are hydrogen. 
 
     
     
         4 . The compound of  claim 3  or pharmaceutically acceptable salt thereof, wherein:
 W is nitrogen; 
 J is independently selected from halogen, —CN, (C1-C6) optionally substituted alkyl, (C3-C9) optionally substituted cycloalkyl, (C1-C6)haloalkyl, —CF 3 , (C1-C6) optionally substituted alkoxy, —NR17R18, optionally substituted heterocyclyl, (C2-C6)alkynyl, (C2-C8)alkenyl and (C1-C6)haloalkyoxy; 
 JJ is independently selected from halogen, —CN, (C1-C6)haloalkyl, (C1-C6) optionally substituted alkyl, —CF 3 , (C1-C6) optionally substituted alkoxy, (C2-C6)alkynyl, (C2-C8)alkenyl and (C1-C6)haloalkyoxy; 
 R14 is independently selected from hydrogen, halogen, (C1-C6) optionally substituted alkyl and —CN. 
 
     
     
         5 . A compound of  claim 4  or a pharmaceutically acceptable salt thereof, wherein:
 J is independently selected from hydrogen, halogen, —CN and (C2-C6)alkynyl; 
 JJ is independently selected from halogen, —CF 3 , and (C1-C6)haloalkyl. 
 
     
     
         6 . A compound of  claim 5  or pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (C10) 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 Q is Q5. 
 
     
     
         8 . A compound of  claim 7  or pharmaceutically acceptable salt thereof, wherein:
 R1, R2, R3 and R4 are hydrogen; 
 R5, R6, R7 and R8 are hydrogen; 
 A is 
 
       
         
           
           
               
               
           
         
         M is 
       
       
         
           
           
               
               
           
         
         E is a single bond. 
       
     
     
         9 . A compound of  claim 8  or pharmaceutically acceptable salt thereof, wherein:
 J is independently selected from halogen, —CN, (C1-C6) optionally substituted alkyl, (C3-C9) optionally substituted cycloalkyl, (C1-C6)haloalkyl, —CF 3 , (C1-C6) optionally substituted alkoxy, —NR17R18, optionally substituted heterocyclyl, (C2-C6)alkynyl, (C2-C8)alkenyl and (C1-C6)haloalkyoxy; 
 JJ is independently selected from halogen, —CN, (C1-C6)haloalkyl, (C1-C6) optionally substituted alkyl, —CF 3 , (C1-C6) optionally substituted alkoxy, (C2-C6)alkynyl, (C2-C8)alkenyl and (C1-C6)haloalkyoxy. 
 
     
     
         10 . A compound of  claim 9  or pharmaceutically acceptable salt thereof, wherein:
 J is independently selected from hydrogen, halogen, —CN and (C2-C6)alkynyl; 
 JJ is independently selected from halogen, —CF 3 , and (C1-C6)haloalkyl. 
 
     
     
         11 . A compound or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A method for the treatment of breast cancer or colon cancer in a subject, comprising administering an effective amount of a compound of  claims 2 ,  4 ,  7 ,  9 ,  11  and  12  or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A pharmaceutical composition, comprising a compound of  claims 2 ,  4 ,  7 ,  9 ,  11  and  12  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.