Local Conformational Constraint in the Design of a Grb2 SH2 Domain Inhibitor

Abstract

Conformational constraint of amino acid side chains can be a powerful means of enhancing biological activity. For SH2 domains, where binding of peptide ligand is critically dependent on the interaction of phosphotyrosyl (pTyr) residues within pTyr-binding pockets, the potential value of conformationally constrained pTyr mimics has not received significant attention [1,2]. Reported is the design and stereoselective synthesis of pipecolic acid analogue 1 (Figure 1), as an orthogonally protected conformationally constrained version of known high affinity pTyr mimic, phosphono-methyl phenylalanine (Pmp). Included, is the utilization of 1 for the preparation of Grb2 SH2 domain-directed ligand 3, as a variant of known high affinity inhibitor 2 [3], which bears “local constraint” within the pTyr-mimicking residue.