Synthesis and structural characterization of a monocarboxylic inhibitor for GRB2 SH2 domain

Bioorg Med Chem Lett. 2021 Nov 1:51:128354. doi: 10.1016/j.bmcl.2021.128354. Epub 2021 Sep 7.

Abstract

A monocarboxylic inhibitor was designed and synthesized to disrupt the protein-protein interaction (PPI) between GRB2 and phosphotyrosine-containing proteins. Biochemical characterizations show compound 7 binds with the Src homology 2 (SH2) domain of GRB2 and is more potent than EGFR1068 phosphopeptide 14-mer. X-ray crystallographic studies demonstrate compound 7 occupies the GRB2 binding site for phosphotyrosine-containing sequences and reveal key structural features for GRB2-inhibitor binding. This compound with a -1 formal charge offers a new direction for structural optimization to generate cell-permeable inhibitors for this key protein target of the aberrant Ras-MAPK signaling cascade.

Keywords: GRB2; Inhibitors; Macrocyclic peptides; Protein-Protein Interaction; Ras-MAPK signaling; SH2 domains; X-ray crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • GRB2 Adaptor Protein / antagonists & inhibitors*
  • GRB2 Adaptor Protein / metabolism
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship
  • src Homology Domains / drug effects

Substances

  • Carboxylic Acids
  • GRB2 Adaptor Protein
  • GRB2 protein, human