Compositions and methods for treating diseases associated with uncontrolled inflammatory responses

Abstract

Methods of treating, controlling or managing diseases associated with uncontrolled inflammatory responses are provided. These methods comprise the administration of small molecule compounds that alter the activity of Tripartite motif containing 8 (TRIM8) in blood monocytes. Also provided are pharmaceutical compositions that comprise small molecule compounds that specifically target the E2-RING domain or the RING-RING dimerization domain of TRIM8 for the treatment, control or management of diseases associated with uncontrolled inflammatory responses.

1 . A method of treating, controlling or managing a disease of cancer, the method comprising:
 altering TRIM8 activity in a subject's myeloid cells by administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising a small molecule compound that targets a TRIM8 E2-RING binding site or a TRIM8 RING-RING dimerization binding site.   
     
     
         2 . The method of  claim 1 , wherein the small molecule compound comprises the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein the small molecule compound comprises the formula: (5E)-1-[(4-methoxyphenyl)methyl]-5-[(naphthalen-1-yl)methylidene]-1,3-diazinane-2,4,6-trione. 
     
     
         4 . The method of  claim 1 , wherein the small molecule compound comprises the formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the small molecule compound comprises the formula: 3-(2H-1,3-benzodioxol-4-yl)-3-(7-ethyl-1H-indol-3-yl)-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-1-one. 
     
     
         6 . The method of  claim 1 , wherein the myeloid cells are blood monocytes. 
     
     
         7 . The method of  claim 1 , wherein the small molecule compound binds the RING-RING dimerization binding site of TRIM8, and wherein the small molecule compound comprises a region comprising a terminal 6-member ring linked to a 5-member ring linked via a flexible linker to a central 6-member aromatic ring motif, which in turn is linked to another terminal 6-member ring. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutical composition is formulated for oral, enteral, parenteral, intravenous, pulmonary, mucosal, sub-mucosal or transdermal administration. 
     
     
         9 . The method of  claim 8 , wherein the pharmaceutical composition contains one or more pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor-imparting agents or pharmaceutically acceptable carriers suitable for oral, enteral, mucosal, sub-mucosal, parenteral, intravenous or transdermal administration. 
     
     
         10 . A pharmaceutical composition having a chemotherapeutic effect, the pharmaceutical composition comprising:
 a small molecule compound that binds TRIM8 E2-RING binding site or TRIM8 RING-RING dimerization binding site.   
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the small molecule compound comprises the formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the small molecule compound comprises the formula: (5E)-1-[(4-methoxyphenyl)methyl]-5-[(naphthalen-1-yl)methylidene]-1,3-diazinane-2,4,6-trione. 
     
     
         13 . The pharmaceutical composition of  claim 10 , wherein the small molecule compound comprises the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The pharmaceutical composition of  claim 10 , wherein the small molecule compound comprises the formula: 3-(2H-1,3-benzodioxol-4-yl)-3-(7-ethyl-1H-indol-3-yl)-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-1-one. 
     
     
         15 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is formulated in form of a capsule, tablet, pill, powder, granule, dragee, lozenge or bead for oral administration in immediate release, sustained release or controlled release form. 
     
     
         16 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is formulated in form of liquid emulsions, solutions, suspensions, syrups or elixirs for oral administration. 
     
     
         17 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is formulated in form of injectable depot for parenteral administration. 
     
     
         18 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is formulated in form of patch or hydrogel for transdermal application.