title: A novel macrocyclic tetrapeptide mimetic that exhibits low-picomolar Grb2 SH2 domain-binding affinity.
abstract: The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that participates in the signaling of numerous oncogenic growth factor receptor protein-tyrosine kinases (PTKs). Presented herein is a 5-methylindolyl-containing macrocyclic tetrapeptide mimetic (5) that binds to Grb2 SH2 domain protein with K(d)=75 pM. This represents the highest affinity yet reported for a synthetic inhibitor against any SH2 domain. In whole cell assays this novel analogue is able to effectively block the association of Grb2 to cognate cytoplasmic erbB-2 at IC(50)<10nM without prodrug derivatization or the addition of carrier peptide motifs. Anti-mitogenic effects against erbB-2-dependent breast cancers are achieved at non-cytotoxic concentrations (IC(50)=0.6 microM). Macrocycle 5 may be representative of a new class of therapeutically relevant Grb2 SH2 domain-directed agents.
authors.affiliation: Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, MD 21702-1201, USA.
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
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: Lindsey R
authors.initials: LR
authors.lastname: Roberts
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fivash
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
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; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D051380:GRB2 Adaptor Protein; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; D007769:Lactams; D063065:Organophosphonates; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C478964:7,16,19-triaza-18-carbamoylmethyl-9-carboxymethyl-14-((5-methylindol-1-yl)methyl)-8,17,20-trioxo-10-(4-phosphonomethylphenyl)spiro(5.14)eicos-11-ene; C495948:GRB2 protein, human