Modulation of androgen receptor expression
Assigneelonis Pharmaceuticals, Inc.
InventorsRobert A. Macleod, Youngsoo Kim, Tianyuan Zhou, Susan M. Freier, Punit Seth, Eric Swayze, Brett Monia
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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.
Claims50
A single-stranded modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising an at least 12 11 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.
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.
A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence consisting of the sequence of SEQ ID NO:
- 35, and is a pharmaceutically acceptable salt selected from the group consisting of sodium and potassium salts, 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;
- wherein the sugars of the three linked nucleosides of the 5′ wing segment are each a constrained ethyl (cEt) sugar;
- wherein the sugars of 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;
- wherein each internucleoside linkage is a phosphorothioate linkage;
- and wherein each cytosine is a 5-methylcytosine.
A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence consisting of the sequence of SEQ ID NO:
- 39 and is a pharmaceutically acceptable salt selected from the group consisting of sodium and potassium salts, 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;
- wherein the sugars of 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;
- wherein the sugars of 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;
- wherein each internucleoside linkage is a phosphorothioate linkage;
- and wherein each cytosine is a 5-methylcytosine.
Dependencies are inferred from the claim text.