Modulation of androgen receptor expression
View Patent ↗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 compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:
a gap segment consisting of 9 linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of four linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; the three linked nucleosides of the 5′ wing segment are each a constrained ethyl (cEt) sugar; the four linked nucleosides of the 3′ wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.
2. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of the sequence of SEQ ID NO: 39, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide comprises:
a gap segment consisting of 7 linked deoxynucleosides;
a 5′ wing segment consisting of four linked nucleosides; and
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; the four linked nucleosides of the 5′ wing segment are a 2′-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5′ to 3′ direction; the five linked nucleosides of the 3′ wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2′-O-methoxyethyl sugar, and a 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; each internucleoside linkage is a phosphorothioate linkage; and each cytosine is a 5-methylcytosine.
3. A composition comprising the compound of claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
4. A combination comprising the compound of claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.
5. The combination of claim 4 , wherein the anti-androgenic agent is MDV3100.
6. A method of treating cancer comprising administering to a subject having cancer a compound or salt of claim 1 or claim 2 , thereby treating cancer in the subject.
7. The method of claim 6 , wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer or bladder cancer.
8. The method of claim 6 , wherein the cancer is castrate-resistant prostate cancer.
9. The method of claim 8 , 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.
10. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a compound or salt of claim 1 or claim 2 and an anti-androgenic agent.
11. The method of claim 10 , wherein the anti-androgenic agent is selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.
12. The method of claim 10 , wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell.
13. The method of claim 10 , wherein the patient is administered an amount of the compound and an amount of anti-androgenic agent that are each or both less in combination than the amount of either the compound or anti-androgenic agent alone effective in inhibiting the growth or proliferation of said prostate cancer cell.
14. A method of inhibiting growth or proliferation of an androgen receptor (AR)-positive breast cancer cell comprising contacting the breast cancer cell with a compound or salt of claim 1 or claim 2 wherein the growth or proliferation of the breast cancer cell is inhibited.
15. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a composition of claim 3 and an anti-androgenic agent.
16. The method of claim 15 , wherein the anti-androgenic agent is selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464.
17. The method of claim 11 , wherein the anti-androgenic agent is MDV3100.
18. The method of claim 17 , wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostatge cancer cell.
19. The method of claim 16 , wherein the anti-androgenic agent is MDV3100.
20. The method of claim 19 , wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell.