Modulation of androgen receptor expression

Patent metadata

Field	Value
Publication number	US-9175291-B2
Application number	US-201314050574-A
Country	US
Kind code	B2
Filing date	Oct 10, 2013
Priority date	Oct 11, 2012
Publication date	Nov 3, 2015
Grant date	Nov 3, 2015

Abstract

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.

First claim

What is claimed:

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.

Assignees

• Isis Pharmaceuticals Inc

Inventors

• Macleod Robert A
• Kim Youngsoo
• Zhou Tianyuan
• Freier Susan M
• Monia Brett

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P13/08

  of the prostate · CPC title

• C12N2310/315

  Phosphorothioates · CPC title