Bivalent Inhibitors of Protein Tyrosine Kinases

Abstract

The majority of protein kinase inhibitors described to date are ATP analogues. However, the selectivity of these species is highly suspect, given the enormous number of ATP-dependent processes that transpire in living cells. Inhibitors that target the protein binding site do not suffer from this disadvantage but exhibit comparatively low inhibitory activity. An alternative approach for the design of protein tyrosine kinase inhibitors is described herein. We have constructed species that simultaneously bind to the active site and the SH2 domain of the Src kinase. Since the region of the inhibitor that associates with the SH2 domain coordinates with relatively high affinity, the overall effect is a substantial enhancement in inhibitory potency (230-fold). This design element offers a strategy to overcome the otherwise poor efficacy of peptide-based protein tyrosine kinase inhibitors.