Protein Kinase Targeted Therapeutics

Abstract

The present invention relates to compositions and methods useful in treating diseases and disorders related to protein kinases. In particular, the present invention relates to compositions and methods useful for targeting protein kinases related to mitogen activated protein kinase (MAPK) pathways (e.g., p38 MAPK, JNK, ERK, and upstream and downstream protein kinases) and/or casein kinase (CK) pathways (e.g., CK1δ, and upstream and downstream protein kinases), and diseases and disorders related to MAPK pathways (e.g., p38 MAPK, JNK, ERK, and upstream and downstream protein kinases) and/or CK pathways (e.g., CK1δ, and upstream and downstream protein kinases).

1 . A composition comprising one or more anti-inflammatory agents and a protein kinase inhibitor, 
 wherein said protein kinase inhibitor inhibits one or more of p38 MAPK, JNK, ERK, and CK1δ,    wherein said protein kinase inhibitor is a compound described by one of the following formulas:                          including salts and both R and S enantiomeric forms and racemic mixtures thereof;    wherein R1, R2, R3, R4, and R6 are independently selected from H, C, CH, CH2, CH3,                          and a substituted or unsubstituted chemical moiety comprising at least one of the following: alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, carboxamide, hydrogen, amino, nitrogen, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, piperazine, cinnoline, cycloaliphatic subgroup, ester, ether, sulfur, phosphorous, oxygen, an aromatic ring, a non-aromatic ring, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having at least 2 carbons;    wherein R5 is H, CH3, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having less than 5 carbons; and    wherein R7 is selected from the group consisting of H, C, CH, CH2, CH3,                          and a substituted or unsubstituted chemical moiety comprising at least one of the following: alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, carboxamide, hydrogen, amino, nitrogen, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, piperazine, cinnoline, cycloaliphatic subgroup, ester, ether, sulfur, phosphorous, oxygen, an aromatic ring, a non-aromatic ring, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having at least 2 carbons.    
   
   
       2 . The composition of  claim 1 , wherein R3 is a chemical moiety comprising an aromatic group and R4 is a chemical moiety comprising an amine group.  
   
   
       3 . The composition of  claim 1 , wherein said compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       4 . The composition of  claim 1 , wherein said one or more anti-inflammatory agents are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), anti-cytokines, imatinib mesylate, sorafenib, sunitinib malate, and anti-chemokines.  
   
   
       5 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a protein kinase inhibitor, 
 wherein said protein kinase inhibitor inhibits one or more of p38 MAPK, JNK, ERK, and CK1δ,    wherein said protein kinase inhibitor is a compound described by one of the following formulas:                          including salts and both R and S enantiomeric forms and racemic mixtures thereof;    wherein R1, R2, R3, R4, and R6 are independently selected from H, C, CH, CH2, CH3,                          and a substituted or unsubstituted chemical moiety comprising at least one of the following: alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, carboxamide, hydrogen, amino, nitrogen, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, piperazine, cinnoline, cycloaliphatic subgroup, ester, ether, sulfur, phosphorous, oxygen, an aromatic ring, a non-aromatic ring, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having at least 2 carbons;    wherein R5 is H, CH3, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having less than 5 carbons; and    wherein R7 is selected from the group consisting of H, C, CH, CH2, CH3,                          and a substituted or unsubstituted chemical moiety comprising at least one of the following: alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, carboxamide, hydrogen, amino, nitrogen, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, piperazine, cinnoline, cycloaliphatic subgroup, ester, ether, sulfur, phosphorous, oxygen, an aromatic ring, a non-aromatic ring, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having at least 2 carbons.    
   
   
       6 . The pharmaceutical composition of  claim 5 , wherein R3 is a chemical moiety comprising an aromatic group and R4 is a chemical moiety comprising an amine group.  
   
   
       7 . The pharmaceutical composition of  claim 5 , wherein said compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       8 . A method of treating a disorder selected from the group consisting of a skin disorder, an intestinal disorder, a lung disorder, interstitial cystitis of the bladder, coronary disease after ischemia-reperfusion injury, acute renal inflammation, bacterial otitis media, chorioretinal vascular disease, aplastic anemia, bone marrow failure syndrome, and cancer, comprising 
 administering an effective amount of a protein kinase inhibitor to a subject suffering from said disorder, wherein said protein kinase inhibitor inhibits one or more of p38 MAPK, JNK, ERK, and CK1δ,    wherein said protein kinase inhibitor is a compound described by one of the following formulas:                          including salts and both R and S enantiomeric forms and racemic mixtures thereof;    wherein R1, R2, R3, R4, and R6 are independently selected from H, C, CH, CH2, CH3,                          and a substituted or unsubstituted chemical moiety comprising at least one of the following: alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, carboxamide, hydrogen, amino, nitrogen, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, piperazine, cinnoline, cycloaliphatic subgroup, ester, ether, sulfur, phosphorous, oxygen, an aromatic ring, a non-aromatic ring, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having at least 2 carbons;    wherein R5 is H, CH3, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having less than 5 carbons; and    wherein R7 is selected from the group consisting of H, C, CH, CH2, CH3,                          and a substituted or unsubstituted chemical moiety comprising at least one of the following: alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, carboxamide, hydrogen, amino, nitrogen, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, piperazine, cinnoline, cycloaliphatic subgroup, ester, ether, sulfur, phosphorous, oxygen, an aromatic ring, a non-aromatic ring, a linear or branched, saturated or unsaturated, a substituted or unsubstituted, aliphatic chain having at least 2 carbons.    
   
   
       9 . The method of  claim 8 , wherein R3 is a chemical moiety comprising an aromatic group and R4 is a chemical moiety comprising an amine group.  
   
   
       10 . The method of  claim 8 , wherein said compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       11 . The method of  claim 8 , wherein said skin disorder is selected from the group consisting of ichthyosis vulgaris, atopic dermatitis, eczema, allergic skin disease, and hypersensitivity reactions.  
   
   
       12 . The method of  claim 8 , wherein said intestinal disorder is selected from the group consisting of bacterial infections, hemorrhagic shock, and diarrhea.  
   
   
       13 . The method of  claim 8 , wherein said lung disorder is selected from the group consisting of acute lung injury after infection, sepsis, thrombin-induced lung injury, lung injury after reperfusion, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory airway diseases.  
   
   
       14 . The method of  claim 8 , wherein said cancer is selected from the group consisting of prostate cancer, breast cancer, skin cancer, brain cancer, leukemia, lymphoma, and multiple myeloma.  
   
   
       15 . The method of  claim 8 , further comprising administering an additional agent for treating said disorder.