title: Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein.
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.
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chu
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Chang
authors.forename: Yun-Ting
authors.initials: YT
authors.lastname: Chou
authors.lastname: Handoko
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Hu
authors.forename: Lee-Chiang
authors.initials: LC
authors.lastname: Lo
authors.forename: Jing-Jer
authors.initials: JJ
authors.lastname: Lin
mesh_terms: D001665:Binding Sites; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D019000:Phosphotyrosine / Q000494:pharmacology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D018909:src Homology Domains
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D019000:Phosphotyrosine