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 activity of a telomerase enzyme comprising contacting the telomerase enzyme 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. A method of inhibiting the activity of a telomerase enzyme in a cell comprising contacting the cell 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.
3. The method of claim 2 , wherein the cell is a cancer cell.
4. A method of inhibiting the activity of a telomerase enzyme in a patient in need thereof 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.
5. The method of claim 4 , wherein the patient has cancer.
6. The method of claim 5 , 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.
7. The method of claim 6 , wherein the cancer is lung cancer.
8. The method of claim 6 , wherein the cancer is a hematologic cancer.
9. The method of claim 8 , wherein the hematologic cancer is myeloma, leukemia, or lymphoma.
10. The method of claim 6 , wherein the cancer is breast cancer.