Method for treating cancer using a combination of chk1 and atr inhibitors

Abstract

The present invention relates to methods of treating cancer in a patient by administering a compound useful as an inhibitor of ATR protein kinase in combination with a compound useful as an inhibitor of Chk1 protein kinase. The aforementioned combination displays a surprising synergistic effect in treating cancer despite the targeted protein kinases being within the same biological pathway. Moreover, the present invention also relates to methods of treating cancer by administering a compound useful as an inhibitor of ATR protein kinase; administering a compound useful as an inhibitor of Chk1 protein kinase; as well as administering a DNA damaging agent to a patient.The compounds utilized in this invention are represented by formula I and formula II:wherein the variables are as defined herein.

1 - 59 . (canceled) 
     
     
         60 . A method of treating cancer in a patient in need thereof consisting of administering to the patient:
 an effective amount of a compound which inhibits ATR protein kinase, wherein the compound which inhibits ATR protein kinase is:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         an effective amount of a compound which inhibits Chk1 protein kinase. 
       
     
     
         61 . The method of  claim 60 , wherein the compound which inhibits Chk1 protein kinase is selected from AZD7762, LY2603618, MK-8776, CHIR-124, and PF-477736. 
     
     
         62 . The method of  claim 61 , wherein the compound which inhibits Chk1 protein kinase is AZD7762. 
     
     
         63 . The method of  claim 60 , wherein the cancer has a determined defect in a base excision repair protein. 
     
     
         64 . The method of  claim 63 , wherein the base excision repair protein is UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3, APE1, APEX2, LIG1, LIG3, XRCC1, PNK, PNKP, PARP1, PARP2, PolB, PolG, FEN1, or Aprataxin. 
     
     
         65 . The method of  claim 60 , wherein the cancer has a determined defect in ATM signaling cascade. 
     
     
         66 . The method of  claim 65 , wherein the defect in ATM signaling cascade is altered expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC 1, H2AX, MCPH1/BRIT1, CTIP, and SMC1. 
     
     
         67 . The method of  claim 60 , wherein the cancer is determined to express a DNA damaging oncogene. 
     
     
         68 . The method of  claim 67 , wherein said cancer has altered expression or activity of one or more of the following: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A and Rb. 
     
     
         69 . The method of  claim 60 , wherein the cancer is breast cancer or lung cancer. 
     
     
         70 . The method of  claim 69 , wherein the cancer is breast cancer. 
     
     
         71 . The method of  claim 70 , wherein the breast cancer is triple negative breast cancer. 
     
     
         72 . The method of  claim 69 , wherein the cancer is lung cancer. 
     
     
         73 . The method of  claim 72 , wherein the lung cancer is non-small cell lung cancer. 
     
     
         74 . The method of  claim 72 , wherein the lung cancer is small cell lung cancer. 
     
     
         75 . The method of  claim 70 , wherein the compound which inhibits Chk1 protein kinase is AZD7762. 
     
     
         76 . The method of  claim 72 , wherein the compound which inhibits Chk1 protein kinase is AZD7762. 
     
     
         77 . The method of  claim 60 , wherein the compound which inhibits ATR protein kinase and the compound which inhibits Chk1 protein kinase are administered sequentially. 
     
     
         78 . The method of  claim 60 , wherein the compound which inhibits ATR protein kinase and the compound which inhibits Chk1 protein kinase are administered simultaneously.