Small molecule inhibitors of stat3 with anti-tumor activity

Abstract

The present invention concerns compounds, compositions containing these compounds, and methods of using these compounds and compositions as inhibitors of Stat3 signaling, Stat3 dimerization, Stat3-DNA binding, Stat5-DNA binding, and/or aberrant cell growth in vitro or in vivo, e.g., as anti-cancer agents for treatment of cancer, such as breast cancer. The compounds of the invention include, but are not limited to, NSC 74859 (S3I-201), NSC 42067, NSC 59263, NSC 75912, NSC 11421, NSC 91529, NSC 263435, and pharmaceutically acceptable salts and analogs of the foregoing. Other non-malignant diseases characterized by proliferation of cells that may be treated using the compounds of the invention, but are not limited to, cirrhosis of the liver; graft rejection; restenosis; and disorders characterized by a proliferation of T cells such as autoimmune diseases, e.g., type 1 diabetes, lupus and multiple sclerosis. The invention further includes an in-vitro screening test for the presence of malignant cells in a mammalian tissue; a method of identifying inhibitors of constitutive Stat3 activation, Stat3-DNA binding, Stat5-DNA binding, and/or Stat3 dimerization; and a method of identifying anti-cancer agents.

1 . A method of treating a proliferation disorder in a subject, comprising administering an effective amount of at least one compound to a subject, wherein the compound is 
       
         
           
           
               
               
           
         
       
       wherein for the compound of formulas A or B:
 each R is independently H or OH; 
 X is CO 2 H, SO 3 H, PO S H, NO 2 , CH 2 CO 2 H, CF 2 CO 2 H, or CF(CO 2 H) 2  tetrazole; and 
 Y is O, NH, NR, CH 2 , CHR, or CR 2 ; 
 
       
         
           
           
               
               
           
         
       
       wherein for the compound of formula C, formula D, formula E, or formula F:
 R 1  is an aliphatic or aromatic group; 
 R 2  is an aliphatic or aromatic group; 
 each X is independently CO, SO 2 , CONH, or alkyl; and 
 Z is alkyl; 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or analog of any of the foregoing. 
     
     
         2 . The method of  claim 1 , wherein the proliferation disorder is cancer. 
     
     
         3 . The method of  claim 2 , wherein the compound is administered locally at the site of a tumor. 
     
     
         4 . The method of  claim 1 , wherein the proliferation disorder is cancer, and wherein the subject is suffering from a tumor and the compound inhibits growth of the tumor. 
     
     
         5 . The method of  claim 1 , wherein the proliferation disorder is a non-malignant disease characterized by aberrant Stat3 activation of cells. 
     
     
         6 . The method of  claim 1 , wherein the compound is administered locally at the site of the proliferation disorder. 
     
     
         7 . The method of  claim 1 , wherein the subject is not suffering from the proliferation disorder, and wherein the compound is administered to delay onset of the proliferation disorder. 
     
     
         8 . The method of  claim 1 , wherein the route of administration is selected from the group consisting of intravenous, intramuscular, oral, and intra-nasal. 
     
     
         9 . The method of  claim 1 , wherein the subject is human or a non-human mammal. 
     
     
         10 . The method of  claim 1 , further comprising identifying the subject as one suffering from the proliferation disorder. 
     
     
         11 . The method according to  claim 1 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the R 1  group or the R 2  group is, independently, H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cylcoalkenyl, heterocycloalkenyl, acyl, aryl, or heteroaryl, any of which may be optionally substituted. 
     
     
         12 . The method according to  claim 1 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the phosphotyrosine mimic is CO 2 H, SO 3 H, PO S H, NO 2 , CH 2 CO 2 H, CF 2 CO 2 H, or CF(CO 2 H) 2  tetrazole. 
     
     
         13 . A method of suppressing the growth of, or inducing apoptosis in, a cell, or inhibiting constitutive activation and/or preventing STAT3 dimerization in a cell, the method comprising contacting the cell with an effective amount of at least one compound, wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or analog of any of the foregoing. 
     
     
         14 . The method of  claim 13 , wherein the cell is a cancer or tumor cell. 
     
     
         15 . The method of  claim 13 , wherein said administering is carried out in vitro. 
     
     
         16 . The method of  claim 13 , wherein said administering is carried out in vivo. 
     
     
         17 . The method of  claim 13 , wherein the cell is a mammalian cancer cell. 
     
     
         18 . The method of  claim 13 , wherein the cell is a human breast cancer cell. 
     
     
         19 . The method of  claim 13 , wherein said compound is S3I-201. 
     
     
         20 . The method according to  claim 13 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the R 1  group or the R 2  group is, independently, H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, acyl, aryl, or heteroaryl, any of which may be optionally substituted. 
     
     
         21 . The method according to  claim 13 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the phosphotyrosine mimic is CO 2 H, SO 3 H, PO S H, NO 2 , CH 2 CO 2 H, CF 2 CO 2 H, or CF(CO 2 H) 2  tetrazole. 
     
     
         22 . A method of disrupting Stat3 DNA-binding or Stat5 DNA-binding, the method comprising contacting the Stat3 or Stat5 with an effective amount of at least one compound, wherein the compound is S3I-201 (shown in  FIG. 7 ), NSC-59263 (shown in  FIG. 8 ), NSC-42067 (shown in  FIG. 9 ), Formula A (shown in  FIG. 10 ), Formula B (shown in  FIG. 11 ), Formula C (shown in  FIG. 12A ), Formula D ( FIG. 12B ), Formula E ( FIG. 12C ), Formula F ( FIG. 12D ), NSC 75912 (shown in  FIG. 50 ), NSC 11421 (shown in  FIG. 49 ), NSC 91529 (shown in  FIG. 51 ), NSC 263435 (shown in  FIG. 48 ), HL2-006-1 (shown in  FIG. 13 ), HL2-006-2 (shown in  FIG. 14 ), HL2-006-3 (shown in  FIG. 15 ), HL2-006-4 (shown in  FIG. 16 ), HL2-006-5 (shown in  FIG. 17 ), HL2-011-1 (shown in  FIG. 18 ), HL2-011-2 (shown in  FIG. 19 ), HL2-011-3 (shown in  FIG. 20 ), HL2-011-4 (shown in  FIG. 21 ), HL2-011-5 (shown in  FIG. 22 ), BG2069-1 (shown in  FIG. 23 ), HL2-011-6 (shown in  FIG. 24 ), HL2-011-7 (shown in  FIG. 25 ), HL2-005 (shown in  FIG. 26 ), HL2-003 (shown in  FIG. 27 ), BG2066 (shown in  FIG. 28 ), BG2074 (shown in  FIG. 29 ), BG3004 (shown in  FIG. 30 ), BG3006A (shown in  FIG. 31 ), BG3006B (shown in  FIG. 32 ), BG3006D (shown in  FIG. 33 ), BG3009 (shown in  FIG. 34 ), RPM381 (shown in  FIG. 35 ), RPM384 (shown in  FIG. 35 ), RPM385 (shown in  FIG. 35 ), RPM405 (shown in  FIG. 36 ), RPM411 (shown in  FIG. 36 ), RPM407 (shown in  FIG. 37 ), RPM412 (shown in  FIG. 37 ), RPM408 (shown in  FIG. 38 ), RPM410 (shown in  FIG. 38 ), RPM415 (shown in  FIG. 39 ), RPM416 (shown in  FIG. 39 ), RPM418 (shown in  FIG. 40 ), RPM418-A (shown in  FIG. 40 ), RPM427 (shown in  FIG. 41 ), RPM431 (shown in  FIG. 42 ), RPM432 (shown in  FIG. 43 ), RPM444 (shown in  FIG. 44 ) RPM448 (shown in  FIG. 44 ), RPM445 (shown in  FIG. 45 ), RPM447 (shown in  FIG. 45 ), RPM452 (shown in  FIG. 46 ), RPM202 (shown in  FIG. 47 ), or a pharmaceutically acceptable salt or analog of any of the foregoing. 
     
     
         23 . A composition of matter comprising a compound or pharmaceutical composition comprising at least one compound, wherein the compound is S3I-201 (shown in  FIG. 7 ), NSC-59263 (shown in  FIG. 8 ), NSC-42067 (shown in  FIG. 9 ), Formula A (shown in  FIG. 10 ), Formula B (shown in  FIG. 11 ), Formula C (shown in  FIG. 12A ), Formula D ( FIG. 12B ), Formula E ( FIG. 12C ), Formula F ( FIG. 12D ), NSC 75912 (shown in  FIG. 50 ), NSC 11421 (shown in  FIG. 49 ), NSC 91529 (shown in  FIG. 51 ), NSC 263435 (shown in  FIG. 48 ), HL2-006-1 (shown in  FIG. 13 ), HL2-006-2 (shown in  FIG. 14 ), HL2-006-3 (shown in  FIG. 15 ), HL2-006-4 (shown in  FIG. 16 ), HL2-006-5 (shown in  FIG. 17 ), HL2-011-1 (shown in  FIG. 18 ), HL2-011-2 (shown in  FIG. 19 ), HL2-011-3 (shown in  FIG. 20 ), HL2-011-4 (shown in  FIG. 21 ), HL2-011-5 (shown in  FIG. 22 ), BG2069-1 (shown in  FIG. 23 ), HL2-011-6 (shown in  FIG. 24 ), HL2-011-7 (shown in  FIG. 25 ), HL2-005 (shown in  FIG. 26 ), HL2-003 (shown in  FIG. 27 ), BG2066 (shown in  FIG. 28 ), BG2074 (shown in  FIG. 29 ), BG3004 (shown in  FIG. 30 ), BG3006A (shown in  FIG. 31 ), BG3006B (shown in  FIG. 32 ), BG3006D (shown in  FIG. 33 ), BG3009 (shown in  FIG. 34 ), RPM381 (shown in  FIG. 35 ), RPM384 (shown in  FIG. 35 ), RPM385 (shown in  FIG. 35 ), RPM405 (shown in  FIG. 36 ), RPM411 (shown in  FIG. 36 ), RPM407 (shown in  FIG. 37 ), RPM412 (shown in  FIG. 37 ), RPM408 (shown in  FIG. 38 ), RPM410 (shown in  FIG. 38 ), RPM415 (shown in  FIG. 39 ), RPM416 (shown in  FIG. 39 ), RPM418 (shown in  FIG. 40 ), RPM418-A (shown in  FIG. 40 ), RPM427 (shown in  FIG. 41 ), RPM431 (shown in  FIG. 42 ), RPM432 (shown in  FIG. 43 ), RPM444 (shown in  FIG. 44 ) RPM448 (shown in  FIG. 44 ), RPM445 (shown in  FIG. 45 ), RPM447 (shown in  FIG. 45 ), RPM452 (shown in  FIG. 46 ), or RPM202 (shown in  FIG. 47 ), or a pharmaceutically acceptable salt or analog of any of the foregoing; and a pharmaceutically acceptable carrier. 
     
     
         24 . The method of  claim 1 , wherein the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 13 , wherein the compunnd of Formula A has the structure: