Extracellular allosteric inhibitor binding domain from a tyrosine kinase receptor

Abstract

The present invention relates to an extracellular binding domain for an allosteric inhibitor, whereby said binding domain is derived from a single membrane span tyrosine kinase receptor. More specifically, the invention relates to an extracellular domain derived from a Fibroblast Growth Factor Receptor (FGFR). It further relates to the use of this domain for the identification of similar domains in the extracellular part of other tyrosine kinase receptors, and to a screening method for identification of a small compound allosteric inhibitor.

1 - 7 . (canceled) 
     
     
         8 . A method for inducing biased antagonism in a tyrosine kinase receptor pathway, the method comprising administering an allosteric inhibitor binding site derived from the extracellular domain of a tyrosine kinase receptor to the pathway. 
     
     
         9 - 13 . (canceled) 
     
     
         14 . The method of  claim 8 , wherein the allosteric inhibitor binding site is derived from a tyrosine kinase receptor with an lg domain. 
     
     
         15 . The method of  claim 14 , wherein the tyrosine kinase receptor is a Fibroblast Growth Factor receptor, a Vascular Endothelial Growth Factor Receptor or a Platelet Derived Growth Factor Receptor, or a homolog, paralog or ortholog thereof. 
     
     
         16 . The method of  claim 8 , wherein the allosteric inhibitor binding site comprises the sequence of SEQ ID NO: 1, or a sequence presenting at least 70%, 80%, 90% or 95% of homology with SEQ ID NO: 1. 
     
     
         17 . The method of  claim 8 , wherein the allosteric inhibitor binding site comprises a frustrated domain. 
     
     
         18 . The method of  claim 17 , wherein the frustrated domain comprises the sequence of SEQ ID NO: 2, or a sequence presenting at least 70%, 80%, 90% or 95% of homology with SEQ ID NO: 2.