JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
The present invention relates to methods and compositions designed for the treatment, management or prevention of cancer. The methods of the invention comprise the administration of an effective amount of one or more inhibitors of JNK in combination with the administration of an effective amount of one or more other agents useful for cancer therapy. The invention also provides pharmaceutical compositions comprising one or more inhibitors of JNK in combination with one or more other agents useful for cancer therapy. In particular, the invention is directed to methods of treatment and prevention of cancer by the administration of an effective amount of one or more inhibitors of JNK in combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies for treatment or prevention of cancer. Also included are methods of treatment of cancer by the administration of one or more inhibitors of JNK in combination with surgery, alone or in further combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies.
1. A method for treating lung cancer or leukemia in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of one or more JNK inhibitors and a therapeutically effective amount of a chemotherapeutic agent, wherein the JNK inhibitor is:
wherein:
(a) -A-R 1 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —NR 8 C(═O)R 9 , —C(═O)NR 8 R 9 , and —O(CH 2 ) b NR 8 R 9 , wherein b is 2 or 3 and R 8 and R 9 are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or R 8 and R 9 taken together with the atom or atoms to which they are bonded form a heterocycle; and
(b) R 2 is 3-triazolyl or 5-tetrazolyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the chemotherapeutic agent is paclitaxel.
3. The method of claim 1 , wherein the chemotherapeutic agent is cyclophosphamide.
4. The method of claim 1 , wherein said leukemia is acute myelocytic leukemia.
5. The method of claim 4 , wherein said acute myelocytic leukemia is myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias or myelodysplastic syndrome.
6. The method of claim 1 , wherein the chemotherapeutic agent is an apoptosis inducing agent.
7. The method of claim 1 , wherein the JNK inhibitor and chemotherapeutic agent are administered concurrently.
8. The method of claim 1 , wherein the JNK inhibitor and chemotherapeutic agent are administered sequentially.