Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein
Journal
Journal of Medicinal Chemistry
Journal Volume
56
Journal Issue
7
Pages
2841-2849
Date Issued
2013
Author(s)
Abstract
Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have incorporated a novel phosphotyrosine mimetic, which is an unusual amino acid carrying a cyclosaligenyl (cycloSal) phosphodiester moiety, into dipeptides to investigate the inhibitory effect on SH2 domain-containing proteins. A plate-based assay was also established to screen for inhibitors that disrupt the interaction between a phosphopeptide of SLAM (signaling lymphocytic activation molecule) and its interacting protein SAP (SLAM-associated protein). We identified a number of inhibitors with IC50 values in the range of 17-35 μM, implying that the cycloSal phosphodiester-carrying amino acid could mimic the phosphotyrosyl residue. Our results also raise the possibility of integrating the newly developed phosphotyrosine mimetic moiety into inhibitors designed for other SH2 domain-containing proteins. ? 2013 American Chemical Society.
SDGs
Other Subjects
CD150 antigen; phosphotyrosine; phosphotyrosine derivative; signaling lymphocyte activation molecule associated protein; unclassified drug; article; binding assay; chemical modification; controlled study; drug mechanism; drug protein binding; drug screening; drug structure; drug synthesis; drug targeting; IC 50; molecular docking; nonhuman; protein protein interaction; signal transduction; Src homology domain; Binding Sites; Intracellular Signaling Peptides and Proteins; Models, Molecular; Molecular Mimicry; Phosphotyrosine; src Homology Domains
Type
journal article