Use of Peptoid-Peptide Hybrids in the Development of She SH2 Domain-Binding Inhibitors

摘要

Shc is a non-catalytic adapter molecule that participates in RAS activation and mitogenic signal transduction by promoting the formation of multimeric protein complexes through the recognition and binding of its Src homolgy 2 (SH2) domain to phosphotyrosyl (pTyr)containing sequences [1]. We have undertaken a program to develop She SH2 domain-binding antagonists as potential non-kinase directed signaling inhibitors. Using a fluorescence anisotropy (FA)-based competition assay that employs the high affinity fluorescein isothiocyanate (FITC)-containing reference peptide 1 (Figure 1), the N-homoallyl-glycinecontaining peptide-peptoid hybrid 2 was identified as a preferred binding motif [2]. The importance of C-terminal hydrophobic character for high She SH2 domain-binding affinity was also shown. To further explore this latter observation, a series of peptoid-peptide hybrids (3) were prepared in which the original Leu residue in 2 was replaced by both natural and unnatural lipophilic amino acid residues (Figure 1).