title: Monocarboxylic-based phosphotyrosyl mimetics in the design of GRB2 SH2 domain inhibitors.
abstract: Three monocarboxylic-containing analogues, O-carboxymethyltyrosine (cmT, 5), 4-(carboxymethyl)phenylalanine (cmF, 6), and 4-(carboxydifluoromethyl)phenylalanine (F2cmF, 7) were utilized as phosphotyrosyl (pTyr) replacements in a high affinity B-bend mimicking platform, where they exhibited IC50 values of 2.5 microM, 65 microM and 28 microM, respectively, in a Grb2 SH2 domain Biacore binding assay. When a terminal N(alpha)-oxalyl axillary was utilized to enhance ligand interactions with a critical SH2 domain Arg67 residue (alphaA-helix), binding potencies increased from 4- to 10-fold, resulting in submicromolar affinity for cmF (IC50 = 0.6 microM) and low micromolar affinity for F2cmF (IC50 = 2 microM). Cell lysate binding studies also showed inhibition of cognate Grb2 binding to the p185erbB-2 phosphoprotein in the same rank order of potency as observed in the Biacore assay. These results indicate the potential value of cmF and F2cmF residues as pTyr mimetics for the study of Grb2 SH2 domains and suggest new strategies for improvements in inhibitor design.
authors: Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: T R
authors: TR
authors: Burke
authors: J
authors: J
authors: Luo
authors: Z J
authors: ZJ
authors: Yao
authors: Y
authors: Y
authors: Gao
authors: H
authors: H
authors: Zhao
authors: G W
authors: GW
authors: Milne
authors: R
authors: R
authors: Guo
authors: J H
authors: JH
authors: Voigt
authors: C R
authors: CR
authors: King
authors: D
authors: D
authors: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002264:Carboxylic Acids / Q000737:chemistry*; D051380:GRB2 Adaptor Protein; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D019000:Phosphotyrosine / Q000737:chemistry*; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002264:Carboxylic Acids; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D019000:Phosphotyrosine