PKM2 ACTIVATORS IN COMBINATION WITH REACTIVE OXYGEN SPECIES FOR TREATMENT OF CANCER
Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a PKM2 activator and an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells to a patient in need thereof.
1 . A method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the following therapeutic agents:
i) a PKM2 activator, or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof; and
ii) an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells upon administration to the patient, or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof
2 . The method of claim 1 , wherein the PKM2 activator has the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein:
R 1 is cycloalkyl, haloalkyl, halo, nitrile or amino;
R 2 is H or halo;
R 3 is alkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or aralkyl
R 4 is aryl or heteroaryl
R 5 and R 6 are each independently H or alkyl.
3 . The method of claim 1 , wherein the PKM2 activator has the following structure (Ia):
or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof,
wherein:
R 15 is halo;
R 16 is H or NH 2 ; and
w is 1 or 2.
4 . The method of claim 1 , wherein the PKM2 activator is selected from Table 1.
5 . The method claim 4 , wherein the PKM2 activator has the following structure:
6 . The method of claims 4 , wherein the PKM2 activator has the following structure:
7 . The method claim 4 , wherein the PKM2 activator has the following structure:
8 . The method of claim 1 , wherein the anti-cancer drug is an anthracycline.
9 . The method of claim 8 , wherein the anti-cancer drug is selected from the group consisting of doxorubicin and daunorubicin.
10 . The method of claim 1 , wherein the anti-cancer drug is a proteasome inhibitor.
11 . The method of claim 10 , wherein the anti-cancer drug is bortezomib.
12 . The method of claim 1 , wherein the anti-cancer drug is a kinase inhibitor.
13 . The method of claims 12 , wherein the anti-cancer drug is sorafenib.
14 . The method of claim 1 , wherein the anti-cancer drug is a HSP90 inhibitor.
15 . The method of claim 14 , wherein the anti-cancer drug is retaspimycin hydrochloride (IPI-504).
16 . The method of claim 1 , wherein the cancer is a hematologic cancer.
17 . The method of claim 16 , wherein the hematologic cancer is selected from acute myelogenous leukemia (AML), multiple myeloma, follicular lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma.
18 . A method for treatment of cancer in a patient in need thereof, the method comprising reducing glutathione levels in cancer cells of the patient and administering to the patient an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells upon administration to the patient.
19 . The method of claim 18 , wherein reducing glutathione levels in cancer cells of the patient comprises administering a PKM2 activator to the patient, wherein the PKM2 activator reduces glutathione levels in cancer cells of the patient, wherein:
(a) the PKM2 activator has the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein:
R 1 is cycloalkyl, haloalkyl, halo, nitrile or amino;
R 2 is H or halo;
R 3 is alkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or aralkyl
R 4 is aryl or heteroaryl
R 5 and R 6 are each independently H or alkyl;
(b) the anti-cancer drug is a proteasome inhibitor, a kinase inhibitor, or a HSP90 inhibitor;
(c) the cancer is a hematologic cancer; or
(d) a combination thereof.
20 . A kit comprising a PKM2 activator, an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells upon administration to the patient, and instructions for administering the PKM2 activator and the anti-cancer drug to a patient in need of treatment of cancer.