Modulation of androgen receptor expression
Certain embodiments are directed to compounds and compositions targeted to human androgen receptor (AR) for inhibiting androgen receptor levels in a cell, which can be useful for methods of treating cancer and inhibiting cancer cell growth or proliferation.
1. A single-stranded modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising an at least 12 contiguous nucleobase portion of SEQ ID NO: 12 or 175, wherein the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1 and comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
2. The single-stranded modified oligonucleotide of claim 1 , wherein each internucleoside linkage is a phosphorothioate linkage.
3. The single-stranded modified oligonucleotide of claim 1 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar.
4. The single-stranded modified oligonucleotide of claim 1 , wherein the modified sugar comprises a bicyclic sugar.
5. The single-stranded modified oligonucleotide of claim 4 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′, 4′-CH2-O-2′, and 4′-(CH2)2-O-2′.
6. The single-stranded modified oligonucleotide of claim 1 , wherein each cytosine is a 5-methylcytosine.
7. The single-stranded modified oligonucleotide of claim 1 , wherein the modified oligonucleotide is 100% complementary to SEQ ID NO: 1.
8. The single-stranded modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, each nucleoside of each wing segment comprises a modified sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine.
9. The single-stranded modified oligonucleotide of claim 8 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar.
10. The single-stranded modified oligonucleotide of claim 8 , wherein the modified sugar comprises a bicyclic sugar.
11. The single-stranded modified oligonucleotide of claim 10 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′, 4′-CH2-O-2′, and 4′-(CH2)2-O-2′.
12. A single-stranded modified oligonucleotide consisting of 16 to 30 linked nucleosides having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 12, 13, 35, 39, 43, 124, 150, 155, 169, or 175, wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
13. The single-stranded modified oligonucleotide of claim 12 , wherein each internucleoside linkage is a phosphorothioate linkage.
14. The single-stranded modified oligonucleotide of claim 12 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar.
15. The single-stranded modified oligonucleotide of claim 12 , wherein the modified sugar comprises a bicyclic sugar.
16. The single-stranded modified oligonucleotide of claim 15 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′, 4′-CH2-O-2′, and 4′-(CH2)2-O-2′.
17. The single-stranded modified oligonucleotide of claim 12 , wherein each cytosine is a 5-methylcytosine.
18. The single-stranded modified oligonucleotide of claim 12 , wherein the modified oligonucleotide is 100% complementary to SEQ ID NO: 1.
19. The single-stranded modified oligonucleotide of claim 12 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, each nucleoside of each wing segment comprises a modified sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine.
20. The single-stranded modified oligonucleotide of claim 12 , wherein the modified oligonucleotide consists of 16 linked nucleosides having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 12, 13, 35, 39, 43, 124, 150, 155, 169, or 175.
21. The single-stranded modified oligonucleotide of claim 20 , wherein each internucleoside linkage is a phosphorothioate linkage.
22. The single-stranded modified oligonucleotide of claim 20 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar.
23. The single-stranded modified oligonucleotide of claim 20 , wherein the modified sugar comprises a bicyclic sugar.
24. The single-stranded modified oligonucleotide of claim 23 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′, 4′-CH2-O-2′, and 4′-(CH2)2-O-2′.
25. The single-stranded modified oligonucleotide of claim 20 , wherein each cytosine is a 5-methylcytosine.
26. The single-stranded modified oligonucleotide of claim 20 , wherein the modified oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 43, 124, 150, 155, 169, or 175, and wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of 3 linked nucleosides; and
a 3′ wing segment consisting of 3 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of each wing segment comprises a constrained ethyl nucleoside; wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage; and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine.
27. A method of treating cancer in a subject comprising administering to the subject the compound of claim 26 , thereby treating cancer in the subject.
28. The method of claim 27 , wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer, or bladder cancer.
29. The method of claim 27 , wherein the cancer is castrate-resistant prostate cancer.
30. The method of claim 29 , wherein the castrate-resistant prostate cancer is resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700, and VT464.