Thienopyrimidines and uses thereof

Abstract

Described herein are thienopyrimidine compounds of Formula (I), and pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Also provided are methods and kits involving the thienopyrimidine compounds or compositions for treating or preventing proliferative diseases such as cancers (e.g., brain tumors such as DIPGs) in a subject. The invention further provides an embryonic stem cell-based tumor cell model, which can be used for drug screening and disease target identification.

1 - 39 . (canceled) 
     
     
         40 . A genetically engineered precursor cell, which is derived from embryonic stem cells and comprises one or more oncogenes. 
     
     
         41 . The genetically engineered precursor cell of  claim 40 , which is derived from human embryonic stem cells. 
     
     
         42 . The genetically engineered precursor cell of  claim 40 , which is a neural precursor cell (NPC). 
     
     
         43 . The genetically engineered precursor cell of  claim 40 , wherein the one or more oncogenes are mutant histone H3 genes. 
     
     
         44 . The genetically engineered precursor cell of  claim 42 , wherein the NPC expresses oncogene encodes a mutant histone H3 that comprises the K27M mutation. 
     
     
         45 . The genetically engineered precursor cell of  claim 44 , wherein the NPC further expresses an oncogene encoding a constitutively active form of PDGFRA. 
     
     
         46 . The genetically engineered precursor cell of  claim 45 , wherein the constitively active form of PDGFRA is the D842V mutant. 
     
     
         47 . The genetically engineered precursor cell of  claim 40 , wherein the precursor cell exhibits a reduced level of p53 as compared to a wild-type counterpart. 
     
     
         48 . The genetically engineered precursor cell of  claim 47 , wherein the precursor cell expresses an interfering RNA that targets p53. 
     
     
         49 . The genetically engineered precursor cell of  claim 48 , wherein the interfering RNA is a small hairpin RNA. 
     
     
         50 . A method of identifying a compound for treating a proliferative disease, comprising:
 i) providing a genetically engineered precursor cell of  claim 40 ;   ii) contacting the genetically engineered precursor cell with a test agent; and   iii) identifying the test agent as an agent for treating a proliferative disease, if the test agent inhibits growth of the genetically engineered precursor cell.   
     
     
         51 . A method of identifying a compound for treating a proliferative disease comprising:
 i) providing a sample comprising MLL or an MLL fusion protein and menin;   ii) contacting a test agent with the sample;   iii) identifying the test agent as an agent for treating a proliferative disease if the test agent inhibits the interaction between the MLL and the menin, or the MLL fusion proteins and the menin.   
     
     
         52 . The method of  claim 50 , wherein the test agent is identified as an agent for treating the proliferative disease, if the IC 50  value of the test agent is lower than 100 μM. 
     
     
         53 . The method of  claim 50 , wherein the test agent is a small molecule. 
     
     
         54 . The method of  claim 50 , wherein the test agent is a macromolecule. 
     
     
         55 . The method of  claim 50 , wherein the test agent is a protein, a DNA, or an RNA. 
     
     
         56 . The method of  claim 50 , wherein the proliferative disease is cancer. 
     
     
         57 . The method of  claim 50 , wherein the proliferative disease is a brain tumor. 
     
     
         58 . The method of  claim 57 , wherein the brain tumor is DIPG. 
     
     
         59 . (canceled)