Combination of kinase inhibitors and uses thereof

Abstract

The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject.

What is claimed is: 
     
         1 . A method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to said subject simultaneously or sequentially a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor according to a first dosing regimen and (b) a therapeutically effective amount of an mTOR inhibitor according to a second dosing regimen, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α 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 β, PI3-kinase γ, and PI3-kinase δ, wherein each dosing regimen independently comprising repeating cycles of a treatment period followed by a rest period, wherein at least one dosing regimen has one rest period of more than 0 day, wherein the disease condition associated with PI3-kinase α and/or mTOR is selected from neoplastic condition, autoimmune disease, inflammatory disease, fibrotic disease or kidney disease. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the neoplastic condition is selected from the group consisting of NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers, renal cell carcinoma, prostate cancer, neuroendocrine cancer, and endometrial cancers. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the first dosing regimen and the second dosing regimen are different. 
     
     
         7 . The method of  claim 1 , wherein the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of at least 1 day followed by a rest period of at least 1 day. 
     
     
         8 . The method of  claim 1 , wherein the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of 2, 3, 4, 5, 6 or 7 consecutive days followed by a rest period of at least 1 day. 
     
     
         9 . The method of  claim 1 , wherein the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of 2, 3, 4, 5, 6 or 7 consecutive days followed by a rest period of at least 3, 4, or 5 consecutive days. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 3 consecutive days followed by a rest period of 4 consecutive days. 
     
     
         12 . The method of  claim 11 , wherein the first dosing regimen and the second dosing regimen are the same and are administered simultaneously. 
     
     
         13 . The method of  claim 1 , wherein the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 5 consecutive days followed by a rest period of 2 consecutive days. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the first and/or the second dosing regimen independently comprises at least one 7-day cycle comprising at least 3 treatment period on alternate days within the 7 days. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the first dosing regimen has a rest period of 0 days. 
     
     
         19 . The method of  claim 18 , wherein the first dosing regimen has a rest period of 0 days, wherein the second dosing regimen comprises at least one 7-day cycle of a treatment period of 5 consecutive days followed by a rest period of 2 consecutive days. 
     
     
         20 - 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein the PI3-kinase α inhibitor is a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
       
         
           
           
               
               
           
         
       
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the mTOR inhibitor is a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 . The method of  claim 1 , wherein the PI3-kinase α inhibitor and/or the mTOR inhibitor are administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally. 
     
     
         36 - 45 . (canceled) 
     
     
         46 . A method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to said subject simultaneously or sequentially a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α 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 β, PI3-kinase γ, and PI3-kinase δ, wherein the clinical and therapeutic effects of the treatment of the disease condition continue for a durability of effect period of at least as long as the administration period. 
     
     
         47 . The method of  claim 46 , wherein the combination comprises a synergistically effective therapeutic amount of PI3-kinase α inhibitor and an mTOR inhibitor, wherein the PI3-kinase α inhibitor and/or the mTOR inhibitor is present in a sub-therapeutic amount. 
     
     
         48 . The method of  claim 46 , wherein the clinical and therapeutic effects are selected from the group consisting of sustained tumor regression, inhibited tumor re-growth, reduction of proliferation, increased apoptosis, or downregulation of activity of a target protein. 
     
     
         49 . The method of  claim 46 , wherein the clinical and therapeutic effects are sustained tumor regression and inhibited tumor re-growth. 
     
     
         50 . The method of  claim 46 , wherein the durability of effect period is at least 30 days. 
     
     
         51 . The method of  claim 46 , wherein the durability of effect period is at least 5 days. 
     
     
         52 . The method of  claim 46 , wherein the PI3-kinase α inhibitor is administered according to a first intermittent dosing regimen comprising repeating cycles of a treatment period followed by a rest period. 
     
     
         53 . The method of  claim 46 , wherein the mTOR inhibitor is administered according to a second intermittent dosing regimen comprising repeating cycles of a treatment period followed by a rest period. 
     
     
         54 . A method of treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to the subject simultaneously or sequentially a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor according to an intermittent regimen effective to achieve (a) higher therapeutic efficacy, (b) similar or better tolerability of the PI3-kinase α inhibitor and/or mTOR inhibitor, and (c) similar or smaller area under the curve, as compared to administering an equivalent dose of the PI3-kinase α inhibitor and/or mTOR inhibitor once daily; wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α 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 β, PI3-kinase γ, and PI3-kinase δ. 
     
     
         55 - 69 . (canceled)