Identification of molecular pathways and methods of use thereof for treating retinal neurodegeneration and other neurodegenerative disorders

Abstract

Drug targets, pathways, kits and methods for treating conditions related to neurodegeneration or ocular disease, are disclosed.

1 .- 22 . (canceled) 
     
     
         23 . A method for inhibiting retinal ganglion cell injury or death, which comprises contacting a retinal ganglion cell with at least one small molecule mixed-lineage kinase (MLK) inhibitor that inhibits the expression or activity of two or more protein kinases, wherein the two or more protein kinases are selected from MAP3K12, MAP3K13, MAP3K14, MAP2K7, MAP2K4, LYN, PLK3, PFKP MARK3, MARK2, TAOK1, IKBKB, BRSK2, PBK, PRKCH, TESK1, Csnk1e, Oxsr1, Tgfbr2, Mapk10, PFTK1, ERN2, AK2, HSPB8, FRAP1, DGUOK, ERN1, STK32B, PIK3C2G, BCR, DYRK1A, DYRK1B, PNCK, EIF2AK1, PKD2L1, NRK, Endothelin Receptor Type B, and TLK2. 
     
     
         24 . The method of  claim 23 , wherein the at least one small molecule MLK inhibitor is a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of H, halogen, alkyl, —OH, —NHCONHC 6 H 5 , CH 2 SOC 2 H 5 , —NHCONHC 2 H 5 , —CH 2 SC 2 H 5 , —CH 2 SC 2 H 5 , —NHCONHC 2 H 5 , —R 3 R 4 , wherein R 3  and R 4  are each H or alkyl, —CH 2 OCONHC 2 H 5 , —NHCO 2 CH 3 , —CH 2 OC 2 H 5 , —CH 2 N(CH 3 ) 2 , —CH 2 SO 2 C 2 H 5 , —CH 2 S—C 5 H 4 N, —CH 2 SC 2 H 5 , —CH═NNH—C 5 N 2 H 5 , —CH 2 S—C 4 N 2 H 3 , —CH 2 S(O)—C 4 N 2 H 3 , —CH 2 S(O)C 5 NH 4 , —CH 2 SC 2 H 5 , O-n-propyl, —CH 2 SCH 2 CH 2 N(CH 3 ) 2 , —CH 2 S-benzimidazole, —CH 2 SCH 2 -furan, —CH═N-pyrrolidine, —CH═NNH-pyridine, —CH 2 S(CH 2 ) 2 NH 2 , —CH 2 -1,2,4-triazole, —CH═NNH—C(═NH)NH 2 , —CH—N-1,2,4-triazole, —CH═N-mopholine, —CHN—N(CH 3 ) 2 , —CH═N-1-methylpiperazine, —CHCH 2 S(CH 2 ) 2 NH-n-C 4 H 9 , and —CH 2 S—(CH 2 ) 2 N(CH 3 ) 2 ; 
         R 2  is selected from the group consisting of H, halogen, —NHCONHC 2 H 5 , —CH 2 SC 2 H 2 , —CH 2 OH, —NH 2 , —CH 2 S(CH 2 ) 2 —N(CH 3 ) 2 ; 
         X is selected from the group consisting of H, —CH 2 N 3 , —CO 2 CH 3 , —CH 2 OH, —CONHC 2 H 5 , —CH═NNH—C 3 N 2 H 5 , —CH 2 NH-Gly, —CON(CH 3 ) 2 , —CH 2 NHCO 2 , —CONH 2 , —CONHCC 3 H 7 , —CH 2 NH-Ser, —CH 2 SOCH 3 , —CH═NOH, —C—O-morpholine, —CH 2 NH-Pro, —CH═NNHC(═NH)NH 2 , —CONH(CH 2 )OH, —CO 2 CH 3 , —CH═NNHCONH 2 , —CH 2 OCOCH 3 , —CONHC 6 H 5 , —CH 2 SO-pyridine, —CH 2 NHCO 2 C 6 H 5 , —CH 2 OH, —CONHC 6 H 5 , —CONHCH 2 CH 2 OH, CH 2 NHCO 2 CH 3 , —CONH 2 , —CH 2 SC 6 H 5 , —CH 2 S-pyridine, —CH 2 SOC 6 H 5 , —CO 2 -n-hexyl, —CH 2 NH 2 , and —CONHCH 3 ; 
         R is selected from the group consisting of —OH and -methoxyl; 
         Z 1  and Z 2  are selected from the group consisting of H and O; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         25 . The method of  claim 24 , wherein the at least one small molecule MLK inhibitor has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 24 , wherein the at least one small molecule MLK inhibitor has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 23 , wherein the at least one small molecule MLK inhibitor is sunitinib or Vx680. 
     
     
         28 . The method of  claim 23 , which comprises contacting the retinal ganglion cell with two small molecule MLK inhibitors. 
     
     
         29 . The method of  claim 23 , wherein the retinal ganglion cell is contacted with the at least one small molecule MLK inhibitor ex vivo or in vivo. 
     
     
         30 . The method of  claim 29 , which further comprises grafting or implanting the retinal ganglion cell into a subject after contacting the cell with the at least one small molecule MLK inhibitor. 
     
     
         31 . The method of  claim 30 , wherein the retinal ganglion cell is in a pharmaceutically acceptable carrier. 
     
     
         32 . The method of  claim 23 , wherein inhibiting retinal ganglion cell injury or death treats an ocular neurodegenerative disease. 
     
     
         33 . The method of  claim 32 , wherein the ocular neurodegenerative disease is selected from glaucoma, retinal degeneration, and age-related macular degeneration.