Modified oligonucleotides for telomerase inhibition
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.
1. A method of inhibiting the proliferation of a cancer cell comprising contacting the cancer cell with a compound having the following structure:
wherein “nps” represents a thiophosphoramidate linkage,
—NH—P(═O)(SH)—O—, connecting the 3′-carbon of one nucleoside to the 5′-carbon of the adjacent nucleoside;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the cancer is skin cancer, connective tissue cancer, adipose cancer, breast cancer, lung cancer, stomach cancer, pancreas cancer, ovary cancer, cervix cancer, uterus cancer, kidney cancer, bladder cancer, colon cancer, prostate cancer, central nervous system (CNS) cancer, retina cancer, or a hematologic cancer.
3. The method of claim 2 , wherein the cancer is lung cancer.
4. The method of claim 2 , wherein the cancer is a hematologic cancer.
5. The method of claim 4 , wherein the hematologic cancer is myeloma, leukemia, or lymphoma.
6. The method of claim 2 , wherein the cancer is breast cancer.
7. A method of treating cancer comprising contacting the cancer with a compound having the structure:
wherein “nps” represents a thiophosphoramidate linkage,
—NH—P(═O)(SH)—O—, connecting the 3′-carbon of one nucleoside to the 5′-carbon of the adjacent nucleoside;
or a pharmaceutically acceptable salt thereof; and
wherein the cancer is skin cancer, connective tissue cancer, adipose cancer, breast cancer, lung cancer, stomach cancer, pancreas cancer, ovary cancer, cervix cancer, uterus cancer, kidney cancer, bladder cancer, colon cancer, prostate cancer, central nervous system (CNS) cancer, retina cancer, or a hematologic cancer.
8. The method of claim 7 , wherein the cancer is lung cancer.
9. The method of claim 7 , wherein the cancer is a hematologic cancer.
10. The method of claim 9 , wherein the hematologic cancer is myeloma, leukemia, or lymphoma.
11. The method of claim 7 , wherein the cancer is breast cancer.
12. A method of inhibiting the proliferation of a cancer in a patient comprising administering to the patient a pharmaceutical composition comprising a compound having the structure:
wherein “nps” represents a thiophosphoramidate linkage,
—NH—P(═O)(SH)—O—, connecting the 3′-carbon of one nucleoside to the 5′-carbon of the adjacent nucleoside;
or a pharmaceutically acceptable salt thereof; and
wherein the cancer is skin cancer, connective tissue cancer, adipose cancer, breast cancer, lung cancer, stomach cancer, pancreas cancer, ovary cancer, cervix cancer, uterus cancer, kidney cancer, bladder cancer, colon cancer, prostate cancer, central nervous system (CNS) cancer, retina cancer, or a hematologic cancer.
13. The method of claim 12 , wherein the cancer is lung cancer.
14. The method of claim 12 , wherein the cancer is a hematologic cancer.
15. The method of claim 14 , wherein the hematologic cancer is myeloma, leukemia, or lymphoma.
16. The method of claim 12 , wherein the cancer is breast cancer.
17. A method of treating cancer in a patient comprising administering to the patient a pharmaceutical composition comprising a compound having the structure:
wherein “nps” represents a thiophosphoramidate linkage,
—NH—P(═O)(SH)—O—, connecting the 3′-carbon of one nucleoside to the 5 ′-carbon of the adjacent nucleoside;
or a pharmaceutically acceptable salt thereof; and
wherein the cancer is skin cancer, connective tissue cancer, adipose cancer, breast cancer, lung cancer, stomach cancer, pancreas cancer, ovary cancer, cervix cancer, uterus cancer, kidney cancer, bladder cancer, colon cancer, prostate cancer, central nervous system (CNS) cancer, retina cancer, or a hematologic cancer.
18. The method of claim 17 , wherein the cancer is lung cancer.
19. The method of claim 17 , wherein the cancer is a hematologic cancer.
20. The method of claim 19 , wherein the hematologic cancer is myeloma, leukemia, or lymphoma.
21. The method of claim 17 , wherein the cancer is breast cancer.