Two separate libraries, prepared via parallel synthesis, were employed to identify low-molecular-weight SH2-targeted ligands for the Lck tyrosine protein kinase. These libraries were constructed to furnish non-amino acid analogues of the (1) Glu-Glu and (2) Ile residues of the Lck SH2 domain peptide ligand Ac-pTyr-Glu-Glu-Ile-amide. The lead compound acquired in this study exhibits a dissociation constant for the Lck SH2 domain that is comparable to that displayed by Ac-pTyr-Glu-Glu-Ile-amide. These results demonstrate that the standard amino acid residues Glu-Glu-Ile can be completely replaced with non-amino acid moieties without loss of SH2 affinity.