Mapkap kinase-2 as a specific target for blocking proliferation of P53-defective cells
The present invention relates to compounds and pharmaceutical compositions for treating cellular proliferative disorders, e.g., in patients having one or more p53-deficient cells, screening assays for identifying such compounds, and methods for treating such disorders.
1. A method for treating a cellular proliferative disorder in a patient having a p53-deficient cell, said method comprising administering to the patient a peptide comprising the amino acid sequence LQRQLSI (SEQ ID NO: 16), wherein the peptide comprises no more than 50 amino acids, and wherein the peptide is capable of inhibiting an activity of a MAPKAP kinase-2 polypeptide.
2. The method of claim 1 , wherein said patient has a tumor, and wherein said peptide is administered to said tumor.
3. The method of claim 2 , wherein said peptide is administered to said tumor by direct injection.
4. The method of claim 2 , wherein said administration results in a reduction in size of said tumor, in comparison to a control patient to whom said peptide is not administered.
5. The method of claim 1 , wherein said administering induces increased sensitivity of said p53-deficient cell to a chemotherapeutic agent, in comparison to a p53-deficient control cell in a control patient to whom said peptide is not administered.
6. The method of claim 5 , wherein said chemotherapeutic agent is selected from the group consisting of alemtuzumab, altretamine, aminoglutethimide, amsacrine, anastrozole, azacitidine, bleomycin, bicalutamide, busulfan, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, 2-chlorodeoxyadenosine, cisplatin, colchicine, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, estramustine phosphate, etodolac, etoposide, exemestane, floxuridine, fludarabine, 5-fluorouracil, flutamide, formestane, gemcitabine, gentuzumab, goserelin, hexamethylmelamine, hydroxyurea, hypericin, ifosfamide, imatinib, interferon, irinotecan, letrozole, leuporelin, lomustine, mechlorethamine, melphalen, mercaptopurine, 6-mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, paclitaxel, pentostatin, procarbazine, raltitrexed, rituximab, rofecoxib, streptozocin, tamoxifen, temozolomide, teniposide, 6-thioguanine, topotecan, toremofine, trastuzumab, vinblastine, vincristine, vindesine, and vinorelbine.
7. The method of claim 5 , wherein said administering alters a DNA damage-responsive cell cycle checkpoint of said p53-deficient cell in comparison to said control cell.
8. The method of claim 7 , wherein said DNA damage-responsive cell cycle checkpoint is G 1 /S phase arrest.
9. The method of claim 8 , wherein Cdc25a degradation in a p53-deficient cell is impaired in comparison to a p53-deficient control cell in a control patient.
10. The method of claim 7 , wherein said DNA damage-responsive cell cycle checkpoint is G 2 /M phase arrest.
11. The method of claim 10 , wherein the interaction between Cdc25b and a 14-3-3 protein is reduced in comparison to a p53-deficient control cell in a control patient.
12. The method of claim 7 , wherein said cell cycle checkpoint alteration induces cell death.
13. The method of claim 12 , wherein said cell death is by apoptosis.
14. The method of claim 13 , wherein said apoptosis is at least partially dependent on caspase-3 activation.