Use of ape1/ref-1 inhibitors in combination therapies for treatment of cancer

Abstract

Combination therapies including a Apurinic/Apyrimidinic Endonuclease/reduction-oxidation (redox) Factor-1 (APE1/Ref-1) inhibitor specific to inhibit the redox function of APE1/Ref-1 are disclosed herein. The Combination therapies can be used for treating various cancers, as well as other angiogenesis-mediated diseases (e.g., retinal diseases, cardiovascular diseases).

1 . A combination therapy comprising an Apurinic/Apyrimidinic Endonuclease/reduction-oxidation (redox) Factor-1 (APE1/Ref-1) inhibitor, wherein the APE1/Ref-1 inhibitor inhibits the redox function of APE1/Ref-1 and a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of a Bcl-2 inhibitor, a PTEN inhibitor, a WNT/β-catenin inhibitor, a pyruvate dehydrogenase (PDH) inhibitor, a α-ketoglutarate dehydrogenase inhibitor, a Notch3 inhibitor, a photodynamic therapy (PDT), and combinations thereof. 
     
     
         2 . The combination therapy as set forth in  claim 1  wherein the APE1/Ref-1 inhibitor is selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide](APX2014) and combinations thereof. 
     
     
         3 . The combination therapy as set forth in  claim 1  wherein the second therapeutic agent is selected from the group consisting of doxorubicin, endostatin, 5-fluorouracil (5-FU), bortezomib, ispinesib mesylate, SN-38, topotecan, paclitaxel, bryostatin 1, trametinib, LAQ824, vinblastine, BEZ235, panobinostat, methotrexate, temsirolimus, FK866, afatinib, tozasertib, irinotecan, GSK2126458, CPI-613, γ-secretase inhibitors, DLL4-inhibiting antibodies, and combinations thereof. 
     
     
         4 . A combination therapy comprising (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide] (APX2014), wherein the APE1/Ref-1 inhibitor inhibits the redox function of APE1/Ref-1, and a second therapeutic agent. 
     
     
         5 . The combination therapy as set forth in  claim 1  wherein the second therapeutic agent is selected from the group consisting of a carbonic anhydrase IX (CA9) inhibitor, signal transduce and activator of transcription 3 (STAT3) inhibitor, platinating agent, and combinations thereof. 
     
     
         6 . The combination therapy as set forth in  claim 5 , wherein the second therapeutic agent is a CA9 inhibitor selected from the group consisting SLC-0111, FC13-555A, FC12-531A, and combinations thereof. 
     
     
         7 . (canceled) 
     
     
         8 . The combination therapy as set forth in  claim 5 , wherein the second therapeutic agent is a STAT3 inhibitor selected from the group consisting of napabucasin, ruxolitinib, and combinations thereof. 
     
     
         9 . (canceled) 
     
     
         10 . The combination therapy as set forth in  claim 5 , wherein the second therapeutic agent is a platinating agent selected from the group consisting of cisplatin, oxaliplatin, carboplatin, and combinations thereof. 
     
     
         11 . (canceled) 
     
     
         12 . The method as set forth in  claim 24 , wherein the cancer is selected from the group consisting of prostate, pancreatic, pancreatic ductal adenocarcinoma, cervical, ovarian, osteosarcoma, germ cell tumor, colon/colorectal, bladder, head and neck, gastric/gastro-esophageal, neuroectodermal tumors, rhabdomyosarcomas, pancreaticobiliary, adult gliomas, non-small cell lung, hepatocellular, multiple myeloma, esophageal, breast, pediatric ependymoma, and melanoma. 
     
     
         13 . The method as set forth in  claim 24 , wherein the cancer is colon cancer, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being selected from the group consisting of doxorubicin, 5-fluorouracil (5-FU), CPI-613, oxaliplatin, napabucasin, CP-839, and combinations thereof. 
     
     
         14 . The method as set forth in  claim 24 , wherein the cancer is leukemia, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being retinoic acid. 
     
     
         15 . The method as set forth in  claim 24 , wherein the cancer is malignant peripheral nerve sheath tumors, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being a survivin inhibitor. 
     
     
         16 . The method as set forth in  claim 24 , wherein the cancer is non-small cell lung carcinoma, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being selected from the group consisting of a Bcl-2 inhibitor, a photodynamic therapy, and combinations thereof. 
     
     
         17 . The method as set forth in  claim 24 , wherein the cancer is prostate cancer, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being a survivin inhibitor. 
     
     
         18 . (canceled) 
     
     
         19 . The method as set forth in  claim 25 , wherein the retinal disease is selected from the group consisting of choroidal neovascularization (CNV), age-related macular degeneration (AMD), retinopathy of prematurity (ROP), diabetic retinopathy (DR)), and ischemic retinopathy. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the combination therapy of  claim 1 . 
     
     
         25 . A method of treating retinal disease in a subject in need thereof, the method comprising administering to the subject the combination therapy of  claim 1 . 
     
     
         26 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject the combination therapy of  claim 1 , wherein the disease is selected from the group consisting of cardiovascular disease, bacterial infection, gastric inflammatory disorder, and neurodegenerative disease. 
     
     
         27 . A method of treating chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need thereof, the method comprising administering to the subject the combination therapy of  claim 1 . 
     
     
         28 . The method as set forth in  claim 27 , wherein the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide](APX2009), (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide] (APX2014) and combinations thereof, and a second therapeutic agent being a platinating agent selected from the group consisting of cisplatin, oxaliplatin, carboplatin, and combinations thereof.