Stat3 inhibitors and uses thereof

Abstract

Described herein, inter alia, are STAT-binding nucleic acids-including compositions and methods of using the same.

1 - 20 . (canceled) 
     
     
         21 . A method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound comprising a toll-like receptor (TLR)-binding nucleic acid substituent conjugated to a signal transducer and activator of transcription (STAT)-binding nucleic acid substituent, wherein the STAT-binding nucleic acid substituent is capable of binding to a STAT transcription factor; and
 wherein the cancer is breast cancer, glioblastoma, ovarian cancer, lung cancer, head and neck cancer, esophageal cancer, skin cancer, melanoma, neuroendocrine cancer, bladder cancer, brain cancer, colorectal cancer, or myeloma.   
     
     
         22 . The method of  claim 21 , wherein the TLR-binding nucleic acid substituent is a toll-like receptor 9 (TLR9)-binding DNA substituent; and wherein the STAT-binding nucleic acid substituent is a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent. 
     
     
         23 . The method of  claim 22 , wherein the TLR9-binding DNA substituent and the STAT3-binding DNA substituent independently comprise an internucleotide linkage selected from the group consisting of a phosphoramidate linkage, a phosphorodiamidate linkage, a phosphorothioate linkage, a phosphorodithioate linkage, a phosphonocarboxylic acid linkage, a phosphonocarboxylate linkage, a phosphonoacetic acid linkage, a phosphonoformic acid linkage, a methyl phosphonate linkage, a boron phosphonate linkage, and a O-methylphosphoroamidite linkage. 
     
     
         24 . The method of  claim 23 , wherein the TLR9-binding DNA substituent and the STAT3-binding DNA substituent comprise a phosphorothioate linkage. 
     
     
         25 . The method of  claim 21 , wherein the TLR-binding nucleic acid substituent is conjugated to the STAT-binding nucleic acid substituent via a linker, wherein the linker comprises a substituted or unsubstituted C 1 -C 20  alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C 3 -C 8  cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C 6 -C 10  arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene 
     
     
         26 . The method of  claim 21 , wherein the TLR-binding nucleic acid substituent is conjugated to the STAT-binding nucleic acid substituent via a linker, wherein the linker comprises an alkylphosphate linker having the structure -L 1a -(PO 4 H-L 2a ) n1 - or L 1a -PO 4   − -L 2a ) n1 -, wherein L 1a  and L 2a  are independently unsubstituted C 1 -C 10  alkylene, and n1 is an integer from 1 to 20. 
     
     
         27 . The method of  claim 21 , wherein the cancer is melanoma, neuroendocrine cancer, or bladder cancer. 
     
     
         28 . The method of  claim 27 , wherein the cancer is melanoma. 
     
     
         29 . The method of  claim 22 , wherein the TLR9-binding nucleic acid substituent comprises SEQ ID NO:23, and wherein the STAT3-binding nucleic acid substituent comprises SEQ ID NO:12. 
     
     
         30 . The method of  claim 22 , wherein the TLR9-binding DNA substituent comprises ODN 1585, ODN 2216, ODN D19, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN 2395, or ODN M362. 
     
     
         31 . The method of  claim 22 , wherein the STAT3-binding DNA substituent comprises a first STAT3-binding DNA sequence covalently bound to a second STAT3-binding DNA sequence by a spacer; wherein the spacer has the structure -L 1 -(PO 4 H-L 2 ) n - or L 1 -(PO 4   − -L 2 ) n -, wherein L 1  and L 2  are independently unsubstituted C 1 -C 10  alkylene, and n is an integer from 1 to 5. 
     
     
         32 . A compound comprising a toll-like receptor 9 (TLR9)-binding DNA substituent conjugated via a linker to a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein the STAT3-binding nucleic acid substituent is capable of binding to a STAT3 transcription factor;
 wherein the TLR9-binding DNA substituent and the STAT3-binding DNA substituent independently comprise an internucleotide linkage selected from the group consisting of a phosphoramidate linkage, a phosphorodiamidate linkage, a phosphorothioate linkage, a phosphorodithioate linkage, a phosphonocarboxylic acid linkage, a phosphonocarboxylate linkage, a phosphonoacetic acid linkage, a phosphonoformic acid linkage, a methyl phosphonate linkage, a boron phosphonate linkage, and a O-methylphosphoroamidite linkage; and   wherein the linker comprises a substituted or unsubstituted C 1 -C 20  alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C 3 -C 8  cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C 6 -C 10  arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.   
     
     
         33 . The compound of  claim 32 , wherein the TLR9-binding DNA substituent comprises a phosphorothioate linkage. 
     
     
         34 . The compound of  claim 32 , wherein the STAT3-binding DNA substituent comprise a phosphorothioate linkage. 
     
     
         35 . The compound of  claim 32 , wherein the linker comprises an alkylphosphate linker having the structure -L 1a -(PO 4 H-L 2a ) n1 - or L 1a -(PO 4   − -L 2a ), wherein L 1a  and L 2a  are independently unsubstituted C 1 -C 10  alkylene, and n1 is an integer from 1 to 5. 
     
     
         36 . The compound of  claim 32 , wherein the TLR9-binding nucleic acid substituent comprises SEQ ID NO:23, and wherein the STAT3-binding nucleic acid substituent comprises SEQ ID NO:12. 
     
     
         37 . The compound of  claim 35 , wherein the TLR9-binding nucleic acid substituent comprises SEQ ID NO:23, and wherein the STAT3-binding nucleic acid substituent comprises SEQ ID NO:12. 
     
     
         38 . The compound of  claim 32 , wherein the TLR9-binding DNA substituent comprises ODN 1585, ODN 2216, ODN D19, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN 2395, or ODN M362. 
     
     
         39 . The compound of  claim 32 , wherein the STAT3-binding DNA substituent comprises a first STAT3-binding DNA sequence covalently bound to a second STAT3-binding DNA sequence by a spacer; wherein the spacer has the structure -L 1 -(PO 4 H-L 2 ) n - or L 1 -(PO 4   − -L 2 ) n -, wherein L 1  and L 2  are independently unsubstituted C 1 -C 10  alkylene, and n is an integer from 1 to 5. 
     
     
         40 . A pharmaceutical composition comprising the compound of  claim 32 .