Alpha-helix mimetics and method relating to the treatment of cancer stem cells

Abstract

The invention provides α-mimetic structures and a chemical library relating thereto. Additionally, the invention provides methods wherein a-mimetic compounds are used to treat cancer stem cells.

1 - 8 . (canceled)  
   
   
       9 . A pharmaceutical composition comprising a compound of the following general formula (I):  
     
       
         
         
             
             
         
       
     
     wherein A is —(C═O)—CHR 3 —, or —(C═O), B is N—R 5 — or —CHR 6 —, D is —(C═O)—(CHR 7 )— or —(C═O)—, E is -(ZR 8 )— or (C═O), G is —(XR 9 ) n —, —(CHR 10 )—(NR 6 )—,—(C═O)—(XR 12 )—, -(or nothing)-, —(C═O)—, X—(C═O)—R 13 , X—(C═O)—NR 13 R 14 , X—(SO 2 )—R 13 , or X—(C═O)—OR 13 , W is —Y(C═O)—, —(C═O)NH—, —(SO 2 )—, —CHR 14 , (C═O)—(NR 15 )—, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X and Z is independently nitrogen or CH, n=0 or 1; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are the same or different and independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers, salts, and prodrugs thereof, and a pharmaceutically acceptable carrier.  
   
   
       10 - 16 . (canceled)  
   
   
       17 . A compound selected from the group consisting of Compounds 1-2217.  
   
   
       18 . A pharmaceutical composition comprising at least one compound of  claim 17 .  
   
   
       19 - 20 . (canceled)  
   
   
       21 . The pharmaceutical composition according to  claim 18  where the composition comprises an effective amount of the compound and a pharmaceutically acceptable carrier.  
   
   
       22 . A compound according to  claim 17  wherein said compound is used in the preparation of a medicament for eradicating pathologic stem cells in cancer therapy.  
   
   
       23 . (canceled)  
   
   
       24 . The compound of  claim 22 , wherein said stem cells are derived from solid tumors.  
   
   
       25 - 26 . (canceled)  
   
   
       27 . The compound according to  claim 17  wherein said compound is used in the preparation of a medicament for achieving the differentiation of pathologic stem cells by causing a switch from CBP/catenin to p300/catenin transcription in cancer therapy.  
   
   
       28 . The compound of  claim 17  wherein said catenin is β-catenin.  
   
   
       29 . The compound of  claim 17  wherein said catenin is γ/p120-catenin.  
   
   
       30 . The compound of  claim 17  wherein said compound inhibits CBP/catenin signaling in cancer stem cells.  
   
   
       31 - 35 . (canceled)  
   
   
       36 . The compound selected according to  claim 17  wherein said compound inhibits CBP/catenin signaling in cancer stem cells thereby inducing differentiation of cancer stem cells and making them more susceptible to apoptosis induced by at least one specific pathway inhibitor.  
   
   
       37 - 39 . (canceled)  
   
   
       40 . The compound according to  claim 17  wherein said compound is used in the preparation of a medicament for achieving the differentiation of pathologic stem cells by causing a switch from CBP/catenin to p300/catenin transcription in cancer therapy, thereby rendering the cancer cell more susceptible to treatment with other pathway-specific inhibitors.  
   
   
       41 . The compound of  claim 40  wherein said pathway-specific inhibitor is selected from the group consisting of imatinib; Her1/Her2 inhibitors; Notch inhibitors; Hedgehog inhibitors; EGF inhibitors; and PI3K pathway inhibitors.  
   
   
       42 - 45 . (canceled)  
   
   
       46 . The compound according to  claim 17  wherein said compound blocks the CBP/β-catenin interaction.  
   
   
       47 - 51 . (canceled)  
   
   
       52 . A method of treating a cancerous condition by administering at least one compound of  claim 17 , wherein the cancerous condition is at least one selected from the group consisting of acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervix cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary (germ cell) cancer, pancreatic cancer, penis cancer, prostate cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginal cancer, cancer of the vulva, and Wilm's tumor.  
   
   
       53 - 55 . (canceled)  
   
   
       56 . A pharmaceutical composition comprising at least one compound of  claim 17 , wherein said pharmaceutical composition is administered by a method selected from the group consisting of capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, hydrophilic ointments, inhalable fluids, eye drops, and suppositories.  
   
   
       57 . A pharmaceutical composition comprising at least one compound of  claim 17 , in combination with at least one cancer chemotherapeutic wherein said cancer chemotherapeutic works by a mechanism other than blocking CPB/catenin interaction.  
   
   
       58 . (canceled)  
   
   
       59 . A method for eliminating teratoma-forming stem cells prior to transplant into a mammalian subject, comprising incubating a stem cell culture with at least one compound of  claim 17 , wherein said compound inhibits CBP-β-catenin interaction and thereby causes stem cell differentiation.  
   
   
       60 - 96 . (canceled)  
   
   
       97 . A method for eliminating teratoma-forming stem cells prior to transplant into a mammalian subject, comprising incubating a stem cell culture with at least one compound of  claim 17 , wherein said compound inhibits CBP-β-catenin interaction and thereby causes stem cell differentiation.  
   
   
       98 . A method for eliminating teratoma-forming stem cells prior to transplant into a mammalian subject, comprising incubating a stem cell culture with a compound of the following general formula (I):  
     
       
         
         
             
             
         
       
     
     wherein A is —(C═O)—CHR 3 —, or —(C═O), B is N—R 5 — or —CHR 6 —, D is —(C═O)—(CHR 7 )— or —(C═O)—, E is -(ZR 8 )— or (C═O), G is —(XR 9 ) n —, —(CHR 10 )—(NR 6 )—,—(C═O)—(XR 12 )—, -(or nothing)-, —(C═O)—, X—(C═O)—R 13 , X—(C═O)—NR 13 R 14 , X—(SO 2 )—R 13 , or X—(C═O)—OR 13 , W is —Y(C═O)—, —(C═O)NH—, —(SO 2 )—, —CHR 14 , (C═O)—(NR 15 )—, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X and Z is independently nitrogen or CH, n=0 or 1; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are the same or different and independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers salts, and prodrugs thereof.