Endogenous and synthetic inhibitors of the Src-family protein tyrosine kinases

Abstract

Src-family kinases (SFKs) are protooncogenic enzymes controlling mammalian cell growth and proliferation. The activity of SFKs is primarily regulated by two tyrosine phosphorylation sites: autophosphorylation of a conserved tyrosine (YA) in the kinase domain results in activation while phosphorylation of the regulatory tyrosine (YT) near the C-terminus leads to inactivation. The phosphorylated YT (pYT) engages in intramolecular interactions that stabilise the inactive conformation of SFKs. These inhibitory intramolecular interactions include the binding of pY T to the SH2 domain and the binding of the SH2-kinase linker to the SH3 domain. Thus, SFKs are active upon (i) disruption of the inhib..