Inhibitors of tyrosine kinase receptor dimerization

Abstract

The teachings relate to methods of identifying inhibitors of dimerization of tyrosine receptor kinases such as EGFR. The methods comprise providing, on a digital computer, a molecular model comprising a complex of extracellular dimerization domains of an RTK, docking a chemical databases to the molecular model, scoring the compounds comprised by the database, and identifying one or more high-scoring compounds. The methods further comprise testing a compound for RTK inhibitory activity in vitro, and testing a compound for specificity as an RTK inhibitor. Also disclosed are compounds selected by the described methods, and methods of treatment using the compounds. Two compounds (NSC11241 and NSC56452) are disclosed that inhibit EGF receptor kinase activation in a dose-dependent manner.

1 . A method of identifying one or more inhibitors of heterodimerization or homodimerization of activated extracellular domains of at least one tyrosine receptor kinase (RTK), the method comprising:
 providing, on a digital computer, a molecular model comprising a complex of extracellular dimerization domains of an RTK;   docking a chemical databases to the molecular model;   scoring the compounds comprised by the database; and   identifying one or more high-scoring compounds.   
   
   
       2 . A method in accordance with  claim 1 , further comprising:
 obtaining at least one high-scoring compound;   testing the at least one high-scoring compound for an ability to inhibit tyrosine kinase activity in target cells.   
   
   
       3 . A method in accordance with  claim 2 , further comprising testing the at least one high-scoring compound for specificity of inhibition of the RTK. 
   
   
       4 . A method in accordance with  claim 3 , further comprising testing the at least one high-scoring compound for an ability to inhibit chemical cross-linking of the RTK when stimulated with its natural ligand 
   
   
       5 . A method in accordance with  claim 1 , wherein the RTK is EGFR. 
   
   
       6 . A method in accordance with  claim 2 , wherein the RTK is EGFR. 
   
   
       7 . A method in accordance with  claim 3 , wherein the RTK is EGFR. 
   
   
       8 . A method in accordance with  claim 4 , wherein the RTK is EGFR. 
   
   
       9 . A novel compound or a salt thereof, selected from the group consisting of an analog of Compound NSC11241 or a salt thereof, an analog of Compound NSC309895 or a salt thereof, an analog of Compound NSC303769 or a salt thereof, and an analog of Compound NSC56452 or a salt thereof, Compound NSC11241 or a salt thereof, Compound NSC309895 or a salt thereof, Compound NSC303769 or a salt thereof, and Compound NSC56452 or a salt thereof, wherein the compound or salt thereof is an inhibitor of RTK dimerization. 
   
   
       10 . A novel compound or a salt thereof in accordance with  claim 9 , wherein the compound or salt thereof is selected from the group consisting of Compound NSC56452 or a salt thereof, Compound NSC11241 or a salt thereof, Compound NSC309895 or a salt thereof, Compound NSC303769 or a salt thereof, and Compound NSC56452 or a salt thereof. 
   
   
       11 . A novel compound or a salt thereof in accordance with  claim 9 , wherein the compound or salt thereof is Compound NSC11241 or a salt thereof. 
   
   
       12 . A novel compound or a salt thereof in accordance with  claim 9 , wherein the compound or salt thereof is Compound NSC56452 or a salt thereof. 
   
   
       13 . A method of inhibiting dimerization of an RTK, the method comprising contacting the RTK with a compound or salt thereof of  claim 9 . 
   
   
       14 . A method of inhibiting dimerization of an RTK in accordance with  claim 13 , wherein the RTK is an EGFR. 
   
   
       15 . A method of inhibiting dimerization of an RTK in accordance with  claim 13 , wherein the compound or salt thereof is selected from the group consisting of Compound NSC11241 or a salt thereof, Compound NSC56452 or a salt thereof, Compound NSC309895 or a salt thereof, and Compound NSC303769 or a salt thereof. 
   
   
       16 . A method of inhibiting dimerization of an RTK in accordance with  claim 13 , wherein the compound or salt thereof is selected from the group consisting of Compound NSC56452 or a salt thereof and Compound NSC11241 or a salt thereof. 
   
   
       17 . A method of inhibiting dimerization of an RTK in accordance with  claim 13 , wherein the RTK is comprised by a cell. 
   
   
       18 . A method of inhibiting dimerization of an RTK in accordance with  claim 17 , wherein the cell is a cancer cell. 
   
   
       19 . A method of inhibiting dimerization of an RTK in accordance with  claim 18 , wherein the cancer cell is a cancer cell in vitro.