Method for treating cancer using a combination of dna damaging agents and atr inhibitors

Abstract

Described herein are methods of treating a proliferative disorder (e.g., cancer) in a patient by administering a DNA damaging agent and between about 12 and about 48 hours later administering to the subject a compound that inhibits ATR protein kinase. Methods of treating a proliferative disorder (e.g., cancer) in a patient by administering a compound that inhibits ATR protein kinase are also described. Exemplary ATR inhibitors are represented by Formulae A-I and A-II:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

1 - 154 . (canceled) 
     
     
         155 . A method of treating a proliferative disorder in a subject, the method comprising:
 administering to a subject in need thereof a DNA damaging agent and between about 12 and about 24 hours later administering to the subject a compound that inhibits ATR protein kinase;   
       wherein the DNA-damaging agent is cisplatin; 
       wherein the compound that inhibits ATR is represented by Formula A-3: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         wherein the proliferative disorder is lung cancer. 
       
     
     
         156 . The method of  claim 155 , wherein the proliferative disorder is non-small cell lung cancer. 
     
     
         157 . The method of  claim 155 , wherein the proliferative disorder has one or more defects in the ATM signaling pathway. 
     
     
         158 . The method of  claim 155 , wherein the cancer has a defect in TP53. 
     
     
         159 . The method of  claim 155 , wherein the compound that inhibits ATR is administered about 16 hours after administration of the DNA damaging agent. 
     
     
         160 . A method of treating a proliferative disorder in a subject, the method comprising:
 administering to the subject in need thereof a platinating agent on day 1 and between about 12 and about 24 hours later administering to the subject a first dose of a compound that inhibits ATR protein kinase; and   administering to the subject in need thereof a second dose of the compound that inhibits ATR protein kinase one week after administration of the first dose;   
       wherein the platinating agent is cisplatin; 
       wherein the compound that inhibits ATR is represented by Formula A-3: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         wherein the proliferative disorder is lung cancer. 
       
     
     
         161 . The method of  claim 160 , wherein the lung cancer is non-small cell lung cancer. 
     
     
         162 . The method of  claim 160 , wherein the lung cancer has one or more defects in the ATM signaling cascade. 
     
     
         163 . The method of  claim 160 , wherein the lung cancer has a defect in TP53. 
     
     
         164 . The method of  claim 160 , wherein the compound that inhibits ATR is administered about 16 hours after administration of the DNA damaging agent. 
     
     
         165 . A method of treating a proliferative disorder in a subject, the method comprising:
 administering to the subject in need thereof gemcitabine and between about 12 and about 24 hours later administering to the subject a compound that inhibits ATR protein kinase;   
       wherein the compound that inhibits ATR is represented by Formula A-3: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein the proliferative disorder is pancreatic cancer. 
       
     
     
         166 . The method of  claim 165 , wherein the pancreatic cancer has a defect in the ATM signaling cascade. 
     
     
         167 . The method of  claim 165 , wherein the pancreatic cancer has a defect in TP53. 
     
     
         168 . The method of  claim 165 , wherein the compound that inhibits ATR is administered about 16 hours after administration of the DNA damaging agent. 
     
     
         169 . A method of treating a proliferative disorder in a subject, the method comprising:
 administering to the subject in need thereof gemcitabine on day 1 and between about 12 and about 24 hours later administering to the subject a first dose of a compound that inhibits ATR protein kinase; and   administering to the subject in need thereof a second dose of the compound that inhibits ATR protein kinase every third day after administration of the first dose;   
       wherein the compound that inhibits ATR is represented by Formula A-3: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         wherein the proliferative disorder is pancreatic cancer. 
       
     
     
         170 . The method of  claim 169 , wherein the pancreatic cancer has one or more defects in the ATM signaling cascade. 
     
     
         171 . The method of  claim 169 , wherein the pancreatic cancer has a defect in TP53. 
     
     
         172 . The method of  claim 169 , wherein the compound that inhibits ATR is administered about 16 hours after administration of the DNA damaging agent.