Modulation of signal transducer and activator of transcription 3 (STAT3) expression
Disclosed herein are antisense compounds and methods for decreasing STAT3 mRNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate hyperproliferative diseases.
1. A single-stranded modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising at least 12 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 245, or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide comprises at least one modified internucleoside linkage, and/or at least one a modified sugar, and/or at least one modified nucleobase.
2. The single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide has a nucleobase sequence comprising the sequence of SEQ ID NO: 245.
3. The single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof wherein the oligonucleotide consists of 12-22 linked nucleosides.
4. The single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide consists of 16 linked nucleosides.
5. The single-stranded oligonucleotide of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide consists of 16 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 245.
6. The single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one internucleoside linkage is a modified internucleoside linkage.
7. The single-stranded oligonucleotide of claim 6 , or a pharmaceutically acceptable salt thereof, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
8. The single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one nucleoside comprises a modified sugar.
9. The single-stranded oligonucleotide of claim 8 , or a pharmaceutically acceptable salt thereof, wherein at least one modified sugar is a bicyclic sugar.
10. The single-stranded oligonucleotide of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the bicyclic sugar comprises a 4′-CH 2 —O-2′ bridge or a 4′-CH(CH 3 )—O-2′ bridge.
11. The single-stranded oligonucleotide of claim 8 , or a pharmaceutically acceptable salt thereof, wherein the modified sugar comprises a 2′-O(CH 2 ) 2 —OCH 3 group or a 2′-O—CH 3 group.
12. The single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one nucleoside comprises a modified nucleobase.
13. The single-stranded oligonucleotide of claim 12 , or a pharmaceutically acceptable salt thereof, wherein the modified nucleobase is a 5′-methylcytosine.
14. The single-stranded oligonucleotide of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:
a 5′-wing consisting of 1 to 5 linked nucleosides;
a 3′-wing consisting of 1 to 5 linked nucleosides;
a gap between the 5′-wing and the 3′-wing consisting of 8 to 12 linked 2′-deoxynucleosides;
and wherein at least one of the 5′-wing and the 3′-wing comprises at least one bicyclic nucleoside or one 2′-substituted nucleoside.
15. The single-stranded oligonucleotide of claim 5 , or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:
a 5′-wing consisting of 3 linked nucleosides;
a 3′-wing consisting of 3 linked nucleosides;
a gap between the 5′-wing and the 3′-wing consisting of 10 linked 2′-deoxynucleosides;
wherein each nucleoside of each of the 5′-wing and the 3′-wing comprises a constrained ethyl nucleoside; wherein each internucleoside linkage is a phosphorothioate linkage; and
wherein each cytosine is a 5′-methylcytosine.
16. A method of treating cancer in a human, comprising administering to the human the single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, thereby treating the cancer.
17. A method of treating cancer in a human, comprising administering to the human the single-stranded oligonucleotide of claim 15 , or a pharmaceutically acceptable salt thereof, thereby treating the cancer.
18. The method of claim 16 or 17 , wherein administering the single-stranded oligonucleotide (i) reduces tumor size in the animal; and/or (ii) reduces tumor volume in the animal; and/or (iii) prolongs survival of the animal.
19. A method of reducing expression of STAT3 in a human, comprising administering to the human the single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof.
20. A composition comprising the single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
21. A composition comprising the single-stranded oligonucleotide of claim 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
22. A method of treating cancer in an animal, comprising administering to the animal the composition of claim 20 or 21 , thereby treating the cancer.
23. The method of claim 22 , wherein administering the composition (i) reduces tumor size in the animal; and/or (ii) reduces tumor volume in the animal; and/or (iii) prolongs survival of the animal.
24. The single-stranded oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the oligonucleotide is covalently linked to a conjugate.
25. The single-stranded oligonucleotide of claim 24 , or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises a carbohydrate group.