MTOR Modulators and Uses Thereof

Abstract

The present invention provides methods and compositions for selective modulation of certain protein kinases, and especially mTor complexes. The methods and compositions are particularly useful in inhibiting mTor selectively for therapeutic applications.

1 . A method for inhibiting cell proliferation comprising contacting a cell with a biologically active agent that selectively inhibits mTorC1 and/or mTorC2 activity relative to one or more type I phosphatidylinositol 3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. 
     
     
         2 . A method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell, comprising contacting a cell with an effective amount of biologically active agent that selectively inhibits both mTorC1 and mTorC2 activity relative to one or more type I phosphatidylinositol 3-kinases (PI3-kinase) as ascertained by a cell-based assay or an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ, and thereby Akt phosphorylation at residues S473 and T308 is simultaneously inhibited. 
     
     
         3 . The method of  claim 1  or  2 , wherein the biologically active agent selectively inhibits both mTorC1 and mTorC2 activity relative to all type I phosphatidylinositol 3-kinases (PI3-kinase) consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. 
     
     
         4 . The method of  claim 1  or  2 , wherein the biologically active agent inhibits mTor activity with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay. 
     
     
         5 .- 6 . (canceled) 
     
     
         7 . The method of  claim 1  or  2 , wherein said biologically active agent inhibits phosphorylation of Akt (S473) and Akt (T308) more effectively than rapamycin when tested at a comparable molar concentration in an in vitro kinase assay. 
     
     
         8 .- 12 . (canceled) 
     
     
         13 . The method of  claim 1  or  2 , wherein the biological active agent competes with ATP for binding to ATP-binding site on mTorC1 and/or mTorC2. 
     
     
         14 .- 17 . (canceled) 
     
     
         18 . A method of substantially inhibiting proliferation of a neoplastic cell comprising contacting the cell with an effective amount of an antagonist that inhibits full activation of Akt in a cell and an anti-cancer agent, wherein said inhibition of cell proliferation is enhanced through a synergistic effect of said antagonist and said anti-cancer agent. 
     
     
         19 . (canceled) 
     
     
         20 . A combination treatment for a subject diagnosed with or at risk of a neoplastic condition, comprising administering to said subject a therapeutically effective amount of an antagonist that substantially inhibits full activation of Akt in a cell and an anti-cancer agent, wherein the efficacy of said treatment is enhanced through a synergistic effect of said antagonist and said anti-cancer agent. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 18  or  20 , wherein the anti-cancer agent is selected from the group consisting of rapamycine, Gleevac, or derivative thereof that inhibits a mammalian target of rapamycine or Gleevac. 
     
     
         23 .- 28 . (canceled) 
     
     
         29 . A method of treating a condition caused by aberrant ion transport across epithelial cells in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a biologically active agent that selectively inhibits mTorC1 and/or mTorC2 activity relative to one or more type I phosphatidylinositol 3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. 
     
     
         30 . The method of  claim 29 , wherein said condition caused by aberrant ion transport across epithelial cells is polycystic kidney disease, hypertension, congestive heart failure, nephrotic syndrome or liver cirrhosis. 
     
     
         31 . The method of  claim 1  or  2  or  29  wherein said biologically active agent is a compound, or pharmaceutically acceptable salt thereof, having one of the formulae: 
       
         
           
           
               
               
           
         
       
       wherein,
 n is an integer from 1 to 5; 
 z is an integer from 1 to 2; 
 R 1 , R 3 , and R 4  are independently hydrogen, halogen, —CN, —CF 3 , —OH, —NH 2 , —SO 2 , —COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  and R 6  are independently hydrogen, halogen, —CN, —CF 3 , —OR 5 , —NH 2 , —SO 2 , —COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 5  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
 
     
     
         32 .- 36 . (canceled)