POTENT DIPEPTIDE INHIBITORS OF THE PP60(C-SRC) SH2 DOMAIN

The design, synthesis, and evaluation of dipeptide analogues as ligand s for the pp60(c-src) SH2 domain are described. The critical binding i nteractions between Ac-Tyr-Glu-N(n-C5H11)(2) (2) and the protein are e stablished and form the basis for our structure-based drug design effo rts. The effects of changes in both the C-terminal (11-27) and N-termi nal (51-69) portions of the dipeptide are explored. Analogues with red uced overall charge (92-95) are also investigated. We demonstrate the feasibility of pairing structurally diverse subunits in a modest dipep tide framework with the goal of increasing the druglike attributes wit hout sacrificing binding affinity.