Modified oligonucleotides for telomerase inhibition
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-009/12
C12N-015/11
C12N-015/113
C12N-005/00
C12N-015/115
C07H-021/02
C07H-021/04
C07C-233/18
A61K-047/54
출원번호
US-0194230
(2016-06-27)
등록번호
US-10196641
(2019-02-05)
발명자
/ 주소
Gryaznov, Sergei
Pongracz, Krisztina
출원인 / 주소
Geron Corporation
대리인 / 주소
Foulds, Glenn J.
인용정보
피인용 횟수 :
0인용 특허 :
77
초록▼
Compounds comprising an oligonucleotide moiety covalently linked to a lipid moiety are disclosed. The oligonucleotide moiety comprises a sequence that is complementary to the RNA component of human telomerase. The compounds inhibit telomerase activity in cells with a high potency and have superior c
Compounds comprising an oligonucleotide moiety covalently linked to a lipid moiety are disclosed. The oligonucleotide moiety comprises a sequence that is complementary to the RNA component of human telomerase. The compounds inhibit telomerase activity in cells with a high potency and have superior cellular uptake characteristics.
대표청구항▼
1. A method of inhibiting the activity of a telomerase enzyme, the method comprising contacting the telomerase enzyme with a compound comprising the structure: O-(x-L)n wherein:O is an oligonucleotide comprising a sequence consisting of:GTTAGGGTTAG;GTTAGGGTTAGAC;GTTAGGGTTAGACAA;GGGTTAGAC;CAGTTAGGG;
1. A method of inhibiting the activity of a telomerase enzyme, the method comprising contacting the telomerase enzyme with a compound comprising the structure: O-(x-L)n wherein:O is an oligonucleotide comprising a sequence consisting of:GTTAGGGTTAG;GTTAGGGTTAGAC;GTTAGGGTTAGACAA;GGGTTAGAC;CAGTTAGGG; orCAGTTAGGGTTAG; wherein the internucleoside linkages of the oligonucleotide O are N3′→P5′ thiophosphoramidate linkages;x is an optional linker;L is a lipid moiety; andn=1 or 2 wherein each (x-L) component is independently covalently conjugated to the 5′ terminus or the 3′ terminus of the oligonucleotide O and wherein if n>1, each (x-L) component is independently selected; or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the telomerase enzyme is in a cell. 3. The method of claim 2, wherein the cell is a cancer cell. 4. The method of claim 1, wherein x comprises an amide bond, a glycerol or an aminoglycerol linker optionally linked to the oligonucleotide O through a 5′- or 3′-linked phosphate group. 5. The method of claim 4, wherein L is a lipid selected from the group consisting of substituted and unsubstituted fatty acids and sterols. 6. The method of claim 5, wherein L is a fatty acid substituted with fluorine. 7. The method of claim 4, wherein L is a substituted or unsubstituted hydrocarbon. 8. The method of claim 7, wherein L is a hydrocarbon substituted with fluorine. 9. The method of claim 1, wherein n=1 and the x-L component is covalently conjugated to the 5′ terminus of the oligonucleotide O. 10. The method of claim 1, wherein n=1 and the (x-L) component is covalently conjugated to the 3′ terminus of the oligonucleotide O. 11. The method of claim 1, wherein n=2, one independently selected (x-L) component is covalently conjugated to the 5′ terminus and one independently selected (x-L) component is covalently conjugated to the 3′ terminus. 12. The method of claim 11, wherein each (x-L) is palmitoylamido-aminoglycerol-thiophosphate. 13. The method of claim 1, wherein each (x-L) component is independently selected from the group consisting of 3′-myristoylamide, 3′-palmitoylamide, 3′-stearoylamide, 5′-cholesterylamido-aminoglycerol-thiophosphate, 5′-palmitoylamido-aminoglycerol-thiophosphate, 3′-palmitoylamido-aminoglycerol-thiophosphate, 3′-palmitoylamido-propyl-thiophosphate, 3′-oleinylamide, 3′-linoleylamide, 5′-C11-teflon-thiophosphate, 5′-C13-teflon-thiophosphate, 5′-palmitoylamido-bis-aminoglycerol-thiophosphate, 3′-cholesterylamido-aminoglycerol-thiophosphate, 5′-stearoylamido-aminoglycerol-thiophosphate and 5′-batyl-thiophosphate. 14. A method of inhibiting the activity of a telomerase enzyme, the method comprising contacting the telomerase enzyme with a compound comprising the structure: O-(x-L)n, wherein:O is TAGGGTTAGACAA wherein the internucleoside linkages of the oligonucleotide O are N3′→P5′ thiophosphoramidate linkages;wherein n=1 or 2, wherein if n>1, each (x-L) component is independently selected, andwherein (x-L) is selected from the group consisting of 3′-myristoylamide, 3′-palmitoylamide, 3′-stearoylamide, 3′-palmitoylamido-propyl-thiophosphate, 3′-oleinylamide, 3′-linoleylamide, 5′-cholesterylamido-aminoglycerol-thiophosphate, 5′-C11-teflon-thiophosphate, 5′-C13-teflon-thiophosphate, 5′-batyl-thiophosphate, 3′-palmitoylamido-aminoglycerol-thiophosphate, 5′-palmitoylamido-bis-aminoglycerol-thiophosphate, 3′-cholesterylamido-aminoglycerol-thiophosphate, 5′-stearoylamido-aminoglycerol-thiophosphate;or a pharmaceutically acceptable salt thereof. 15. The method of claim 14, wherein the telomerase enzyme is in a cell. 16. The method of claim 15, wherein the cell is a cancer cell. 17. The method of claim 14, wherein n=1. 18. The method of claim 17, wherein L is directly linked to the 3′ terminus of the oligonucleotide L through an amide bond. 19. The method of claim 17, wherein the compound comprises the following structure: or a pharmaceutically acceptable salt thereof.
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이 특허에 인용된 특허 (77)
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