Methods and use of compounds that bind to rela of nf-kb

Abstract

The invention provides methods and agents that modulate RelA activity. These methods and modulators of RelA activity can be used to treat cancer progression of basal-like breast cancer, such as triple-negative breast cancer.

What is claimed is: 
     
         1 . A method for inhibiting or decreasing or reducing RelA activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of:
 (a) a compound of Formula I:   
       
         
           
           
               
               
           
         
         wherein: 
         a is 0, 1, 2 or 3; 
         R 11  and R 12  can be same or different, and are independently hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 13  is independently for each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 14  is hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; and 
         stereoisomers and pharmaceutically acceptable salts thereof, 
         (b) a compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         wherein: 
         b and g can be same or different and are independently 0, 1, 2, 3, 4 or 5; 
         d is 0, 1 or 2; 
         f is 0, 1, 2, 3 or 4; 
         R 21 , R 24  and R 25  can be all same or all different or two same and one different, and independently for each occurrence hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 22  is independently for each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted, or two R 22  together with the carbon atoms they are attached to form an optionally substituted 5-8 membered cyclyl, heterocylyl, aryl or heteroaryl; 
         R 23  is hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; and 
         stereoisomers and pharmaceutically acceptable salts thereof 
         (c) a compound of Formula (III): 
       
       
         
           
           
               
               
           
         
         wherein: 
         h is 0, 1, 2, 3 or 4; 
         j is 0, 1, 2, 3 or 4; 
         k is 0, 1, 2, 3 or 4; 
         R 31 , R 32  and R 33  can all be same or all different or two are same, and are independently for each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; and 
         stereoisomers and pharmaceutically acceptable salts thereof, 
         (d) a compound of Formula (IV): 
       
       
         
           
           
               
               
           
         
         wherein: 
         m is 0, 1, 2, or 3; 
         n is 0, 1, 2, 3 or 4; 
         R 41  is hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 42  is independently for each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 43  is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 44 , R 45  and R 46  can be same or different, and are independently for each occurrence absent, hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, sulfinyl, sulfonyl, carbonyl, carboxy, thiocabonyl, thio, alkylthio, arylthio or CF 3 , each of which can be optionally substituted, provided that at least one of R 44  and R 46  is not absent; 
         R 47  is independently for each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; and 
         stereoisomers and pharmaceutically acceptable salts thereof, 
         or 
         (e) a compound of Formula (V): 
       
       
         
           
           
               
               
           
         
         wherein: 
         p and q are same or different and are independently 0, 1, 2, or 3; 
         R 51  is hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 52  is independently for each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; 
         R 53 , R 54  and R 55  can be all same, all different or two are same, and are independently for each occurrence hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, sulfinyl, sulfonyl, carbonyl, carboxy, thiocabonyl, thio, alkylthio, arylthio or CF 3 , each of which can be optionally substituted; 
         R 56  is independently for each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or CF 3 , each of which can be optionally substituted; and 
         stereoisomers and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the subject is need of treatment for a cancer or a cancerous condition or a tumor. 
     
     
         3 . The method of  1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 2 , further comprising the step of selecting the subject having a cancer, a cancerous condition, or a tumor. 
     
     
         5 . The method of  claim 4 , wherein the cancer is a breast cancer, squamous cell cancer, lung cancer, a cancer of the peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer, a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer, an endometrial or uterine carcinoma, a salivary gland carcinoma, a kidney or renal cancer, a prostate cancer, a vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell lymphoma, a chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia (ALL), a Hairy cell leukemia, or a chronic myeloblasts leukemia. 
     
     
         6 . The method of  claim 5 , wherein the cancer is a breast cancer. 
     
     
         7 . The method of  claim 6  wherein the cancer is a triple negative breast cancer. 
     
     
         8 . The method of  claim 2 , further comprising administering one or more additional anti-cancer therapies. 
     
     
         9 . The method of  claim 8 , wherein the additional anti-cancer therapy comprises surgery, radiation therapy, biotherapy, immunotherapy, or chemotherapy. 
     
     
         10 . The method of  claim 2 , further comprising administering one or more anti-cancer therapeutic agents. 
     
     
         11 . The method of  claim 10 , wherein the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitor agent, an anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent, or a cytokine. 
     
     
         12 . The method of  claim 1 , wherein the compound is formulated in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient or carrier. 
     
     
         13 . The method of  claim 1 , wherein the compound is formulated in a nanoparticle. 
     
     
         14 . The method of  claim 13 , wherein the nanoparticle is formulated in a pharmaceutical composition comprising the nanoparticle and a pharmaceutically acceptable excipient or carrier.