Inhibitors of ribonucleotide reductase subunit 2 and uses thereof
The present application relates to inhibitors of ribonucleotide reductase subunit 2 (R2), and methods and compositions related to the R2 inhibitors. In certain embodiments, the R2 inhibitors include nucleic acids, such as for example siRNAs.
1. A nucleic acid consisting of:
(i) a first strand consisting of SEQ ID NO. 63 and
(ii) a second strand consisting of SEQ ID NO. 64,
wherein at least 12 nucleotides of the first and second strands are complementary to each other and form a double-stranded nucleic acid under physiological conditions, and wherein the double-stranded nucleic acid can reduce the expression of a ribonucleotide reductase subunit 2 (R2) in a cell by an RNA interference mechanism.
2. The nucleic acid of claim 1 , wherein the nucleic acid comprises one or more modified backbone or base moieties.
3. The nucleic acid of claim 2 , wherein the modified backbone or base moieties are one or more of the following: alkylphosphonates, phosphorothioates, phosphorodithioates, alkylphosphonothioates, phophoramidates, phosphate esters, carbamates, acetamidate, carboxylmethyl esters, carbonates, and phosphate triesters.
4. The nucleic acid of claim 2 , wherein the nucleic acid comprises at least one 2′-O-alkylated ribonucleotide.
5. An isolated double-stranded nucleic acid consisting of a first strand consisting of SEQ ID NO: 63 and a second strand consisting of SEQ ID NO: 64, wherein said second strand hybridizes to a region of an R2 transcript corresponding to nucleotides 616-667 of SEQ ID NO: 1 under physiological conditions and decreases the expression of R2 in a cell.
6. A pharmaceutical composition comprising the nucleic acid of claim 1 or 5 , and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable carrier includes a cationic polymer.
8. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable carrier includes a cyclodextrin polymer.
9. The pharmaceutical composition of claim 6 , further comprising a ligand that targets a particular tissue or cell type.
10. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable carrier comprises:
a cyclodextrin-containing cationic polymer, and
a targeting moiety comprising adamantane-PEG-ligand,
wherein the polymer and targeting moiety form nanoparticles that encapsulates the nucleic acid.
11. A method for inhibiting the growth of a tumor in a patient having a tumor comprising administering to the patient a therapeutically effective amount of the double-stranded nucleic acid of claim 1 or 5 .
12. The method of claim 11 , wherein the nucleic acid is formulated with a pharmaceutically acceptable carrier.
13. The method of claim 11 , wherein the nucleic acid is formulated with a ligand targeting the cancer cell.
14. The method of claim 11 , further including at least one additional anti-cancer chemotherapeutic agent that inhibits cancer cells in an additive or synergistic manner with the nucleic acid.