Treatment of solid tumors by inhibiting MRK/ZAK
Methods and compounds are described for treating solid tumors, and in particular, malignant, neoplastic solid tumors such as glioblastoma and medulloblastoma, by inhibiting protein kinase MRK/ZAK activity. Also provided are pharmaceutical composition containing a MRK/ZAK inhibitor compound and a pharmaceutically acceptable carrier and a method of sensitizing tumor cells to radiation therapy comprising administering an effective amount of the MRK/ZAK inhibitor compound.
1. A method for treating a subject with a glioma or a medulloblastoma comprising administering to the subject a compound in an amount effective to inhibit protein kinase MRK and to sensitize the glioma or medulloblastoma to radiation therapy, wherein the compound inhibits protein kinase MRK at a dose that does not inhibit BCR-Abl.
2. The method of claim 1 , wherein the compound has a molecular weight of 2,000 daltons or less.
3. A method for treating a subject with a glioma or a medulloblastoma comprising administering to the subject a compound in an amount effective to inhibit protein kinase MRK and to sensitize the glioma or medulloblastoma to radiation therapy, wherein the compound has the structure
or an enantiomer or a mixture of enantiomers thereof, or a hydrate thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is an irreversible inhibitor of MRK.
5. The method of claim 1 , wherein the subject is treated with a combination of the protein kinase MRK inhibitor and radiotherapy.
6. The method of claim 5 , wherein the subject is treated with ionizing radiation.
7. The method of claim 1 , wherein the subject has a glioblastoma.
8. The method of claim 1 , wherein the subject has a medulloblastoma.
9. A compound having the structure
or an enantiomer or a mixture of enantiomers thereof, or a hydrate thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable carrier.
11. A radiosensitizer comprising the compound of claim 9 .
12. A method for treating a subject with a glioma or a medulloblastoma comprising administering to the subject the compound of claim 9 in combination with radiation therapy, wherein the compound is administered in an amount effective to sensitize the glioma or medulloblastoma to the radiation therapy.
13. The method of claim 12 wherein the radiation therapy comprises ionizing radiation.
14. The method of claim 12 , wherein the subject has a glioblastoma.
15. The method of claim 12 , wherein the subject has a medulloblastoma.
16. The method of claim 1 , wherein the subject has an astrocytoma.
17. The method of claim 12 , wherein the subject has an astrocytoma.