title: Macrocyclization in the design of non-phosphorus-containing Grb2 SH2 domain-binding ligands.
abstract: Macrocyclization from the phosphotyrosyl (pTyr) mimetic's beta-position has previously been shown to enhance Grb2 SH2 domain-binding affinity of phosphonate-based analogues. The current study examined the effects of such macrocyclization using a dicarboxymethyl-based pTyr mimetic. In extracellular assays affinity was enhanced approximately 5-fold relative to an open-chain congener. Enhancement was also observed in whole-cell assays examining blockade of Grb2 binding to the erbB-2 protein-tyrosine kinase.
authors.affiliation: Laboratory of Medicinal Chemistry, CCR, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Wei
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Hongpeng
authors.initials: H
authors.lastname: Liu
authors.forename: Manchao
authors.initials: M
authors.lastname: Zhang
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Roberts
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D045744:Cell Line, Tumor; D003500:Cyclization; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C485116:3-(2-amino-2-oxoethyl)-1,4,7-triaza-10-(4-(dicarboxymethyl)phenyl)-14-(1-naphthyl)-2,5,8-trioxo-6-pentamethylenecyclopentadecane-9-acetic acid; C495948:GRB2 protein, human