Inhibitory oligonucleotides and their use in therapy

Patent metadata

Field	Value
Publication number	US-2016355822-A1
Application number	US-201615244879-A
Country	US
Kind code	A1
Filing date	Aug 23, 2016
Priority date	Jan 14, 2013
Publication date	Dec 8, 2016
Grant date	—

Abstract

Inhibitory oligonucleotide having the general formula:
X 1 CCN 1 N 2 N 3 X 2 N 4 N 5 GGGN 6 X 3 N 7   (I)

are disclosed which can be used in pharmaceutical compositions, whereby in formula (I)
C is cytidine or a derivative thereof, whereby the cytidine derivative is selected from the group consisting of 5-methylcytidine, a cytidine-like nucleotide having a chemical modification involving the cytosine base, cytidine nucleoside sugar, or both the cytosine base and the cytidine nucleoside sugar, 2′-O-methylcytidine, 5-bromocytidine, 5-hydroxycytidine, ribocytidine and cytosine-β-D-arabinofuranoside, G is guanosine or a derivative thereof, whereby the guanosine derivative is selected from the group consisting of 7-deazaguanosine, a guanosine-like nucleotide having a chemical modification involving the guanine base, the guanosine nucleoside sugar or both the guanine base and the guanosine nucleoside sugar, X 1 and X 3 is any nucleotide sequence with 0 to 12 bases and each nucleotide is independent of any other, X 2 is any nucleotide sequence having 0 to 3 nucleotides, N 1 , N 2 and N 3 are each independently any nucleotide, N 4 and N 7 is a pyrimidine or a modified pyrimidine, N 5 is a purin or a modified purin, N 6 is a modified pyrimidine, A or a modified purin, wherein at least two of the nucleotides N 4 , N 5 , N 6 or N 7 are modified purins or modified pyrimidines.

First claim

1 . An inhibitory oligonucleotide having the general formula (I):
X 1 CCN 1 N 2 N 3 X 2 N 4 N 5 GGGN 6 X 3 N 7   (I)
wherein:
C is cytidine or a derivative thereof, whereby the cytidine derivative is selected from the group consisting of 5-methylcytidine; a cytidine-like nucleotide having a chemical modification involving the cytosine base, cytidine nucleoside sugar, or both the cytosine base and the cytidine nucleoside sugar; 2′-O-methylcytidine; 5-bromocytidine; 5-hydroxycytidine; ribocytidine; and cytosine-β-D-arabinofuranoside,
G is guanosine or a derivative thereof, whereby the guanosine derivative is selected from the group consisting of 7-deazaguanosine; a guanosine-like nucleotide having a chemical modification involving the guanine base, the guanosine nucleoside sugar or both the guanine base; and the guanosine nucleoside sugar,
X 1 and X 3 are each independently any nucleotide sequence with 0 to 12 bases,
X 2 is any nucleotide sequence having 0 to 3 nucleotides,
N 1 , N 2 and N 3 are each independently any nucleotide,
N 4 and N 7 is a pyrimidine or a modified pyrimidine,
N 5 is a purine or a modified purine, and
N 6 is a modified pyrimidine, A or a modified purine,
wherein at least two of the nucleotides N 4 , N 5 , N 6 or N 7 are modified purines or modified pyrimidines.

2 . The inhibitory oligonucleotide according to claim 1 having the general formula (I) set forth therein, wherein:
C is cytidine or a derivative thereof as defined in claim 1 ,
G is guanosine or a derivative thereof as defined in claim 1 ,
X 1 and X 3 are each independently any nucleotide sequence with 0 to 6 bases,
X 2 is 0 or 1 nucleotide,
N 1 , N 2 and N 3 are each independently any nucleotide,
N 4 and N 7 is a pyrimidine or a modified pyrimidine,
N 5 is a purine or a modified purine, and
N 6 is a modified pyrimidine, A or a modified purine,
wherein at least two of the nucleotides N 4 , N 5 , N 6 or N 7 are modified purines or modified pyrimidines, and whereby the oligonucleotide comprises 20 nucleosides or less.

3 . The inhibitory oligonucleotide according to claim 1 , wherein said oligonucleotide has the general formula (II):
N 1 CCTGG pypu GGG px AG py   (II)
in which:
C is cytidine or a derivative thereof as defined in claim 1 ,
G is guanosine or a derivative thereof as defined in claim 1 ,
N 1 is any nucleotide or no nucleotide,
py is a pyrimidine or a modified pyrimidine nucleotide,
pu is a purine or a modified purine nucleotide, and
px is a modified pyrimidine, A or a modified purine,
wherein at least two of the nucleotides py, pu and px are modified purines or modified pyrimidines selected from the group consisting of 7-deaza-desoxyguanosine, 7-deaza-2′-O-methylguanosine, inosine, diaminopurin, 6-thio-desoxyguanosine, 6-O-methyl-desoxyguanosine, 7-deaza-inosine, 7-deaza-7-iododesoxyguanosine, 7-aminopropargyldesoxaguanosine, 2-fluoro-cytosine, 5-methylcytosine.

4 . The inhibitory oligonucleotide according to claim 3 , wherein said oligonucleotide has the general formula (III):
N 1 CCTGG pypu GGG  (III)
in which C, G, N 1 , py, and pu have the meaning as defined in claim 3 .

5 . The inhibitory oligonucleotide according to claim 3 , wherein:
Py is 5-substituted cytidine selected from the group consisting of 5-methyl-dC, 5-bromo-dC and 5-octadienyl-dC, and Pu is a 7-deaza purine derivative selected from the group consisting of 7-deaza-dG, 7-deaza-2′-O-methyl-G, inosine and 7-deaza-inosine and Px is dA or 5-iodo-dU.

6 . The inhibitory oligonucleotide according to claim 1 , characterized in that said oligonucleotide has the sequence dC*dC*dT*dG*dG*dZ*mE*dG*dG*dG*dA*dA*dG*dT.

7 . The inhibitory oligonucleotide according to claim 1 , characterized in that said oligonucleotide has the sequence dC*dC*dT*dG*dG*BC*dE*dG*dG*dG*JU*dA*dG*dT.

8 . An inhibitory oligonucleotide having the general formula (IV):
X 1 AATGG pypu GGG px AG py   (IV)
wherein:
Py is 5-substituted cytidine selected from the group consisting of 5-methyl-dC, 5-bromo-dC and 5-octadienyl-dC,
Pu is a 7-deaza purine derivative selected from the group consisting of 7-deaza-dG, 7-deaza-2′-O-methyl-G, inosine and 7-deaza-inosine,
Px is dA, 5-substituted deoxyuridine, or 5-iodo-uridine, and
X 1 is any nucleotide or no nucleotide.

9 . The inhibitory oligonucleotide according to claim 1 , wherein said oligonucleotide comprises a TLR antagonist having strongly enhanced potency.

10 . A pharmaceutical composition comprising at least one inhibitory oligonucleotide according to claim 1 .

11 . The pharmaceutical composition according to claim 10 , wherein said composition further comprises at least one additive and/or carrier.

13 . The pharmaceutical composition according to claim 10 , wherein said composition is formulated for the treatment of cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, skin disorders, allergy, asthma or a disease caused by a pathogen in a subject in need thereof.

Assignees

• Sarepta Therapeutics Inc

Inventors

• Uhlmann Eugen
• Jurk Marion
• Lehmann Thomas

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title