A novel macrocyclic tetrapeptide mimetic that exhibits low-picomolar Grb2 SH2 domain-binding affinity

Zhen Dan Shi, Kyeong Lee, Hongpeng Liu, Manchao Zhang, Lindsey R. Roberts, Karen M. Worthy, Matthew J. Fivash, Robert J. Fisher, Dajun Yang, Terrence R. Burke

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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 Kd=75pM. 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 IC50< 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 (IC50=0.6μM). Macrocycle 5 may be representative of a new class of therapeutically relevant Grb2 SH2 domain-directed agents.

Original languageEnglish
Pages (from-to)378-383
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume310
Issue number2
DOIs
StatePublished - 17 Oct 2003

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