A shikonin derivative, ??-hydroxyisovalerylshikonin, is an ATP-non-competitive inhibitor of protein tyrosine kinases

Studies of the mechanism of action of a shikonin derivative, β-hydroxyisovalerylshikonin (β-HIVS), have revealed that β-HIVS inhibits the protein tyrosine kinase (PTK) activities of the receptor for epidermal growth factor and v-Src. In this review, we compare the characteristics of the inhibition of PTK activity by β-HIVS with those of other inhibitors of PTKs. The chemical structure of β-HIVS is completely different from that of ATP and it does not resemble any of the PTK inhibitors reported to date, except that it includes the benzilidene moiety. In contrast to most PTK inhibitors, the mechanism of inhibition by β-HIVS is non-competitive with respect to ATP, but competitive with respect to its peptide substrate. This feature of the mechanism of inhibition of PTK by β-HIVS suggests that it might be useful in a clinical setting with other PTK inhibitors. When Bcr–Abl-positive, human leukemia K562 cells were treated simultaneously with β-HIVS and STI571 (Gleevec), these compounds had a synergistic effect on both the induction of apoptosis in K562 cells and the inhibition of the phosphorylation activity of PTK, probably because the mechanism of interference with phosphorylation by β-HIVS and the binding site of β-HIVS are different from those of STI571.