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 (Y(A)) in the kinase domain results in activation while phosphorylation of the regulatory tyrosine (Y(T)) near the C-terminus leads to inactivation. The phosphorylated Y(T) (pY(T)) 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 ..