Selective GRB2 SH2 inhibitors as anti-Ras therapy

Int J Cancer. 1999 Oct 8;83(2):235-41. doi: 10.1002/(sici)1097-0215(19991008)83:2<235::aid-ijc15>;2-b.


Given the key role of Ras in the mitogenic signaling by receptor tyrosine kinases, several targets upstream of Ras may prove to be excellent targets for drugs in the treatment of cancer caused by oncogenic tyrosine kinases. CGP78850 is a potent competitor of Grb2 SH2-phosphopeptide interactions. This inhibitor has been obtained by rational drug design and is specific toward the Grb2 SH2 vs. other SH2 domains and the PTB domain of SHC in vitro. Accordingly, CGP78850 blocks epidermal growth factor receptor (EGFR)-Grb2 and Shc-Grb2 interactions in living cells. It also inhibits the growth of cells transformed by receptor tyrosine kinases, which transmit a proliferative signal through Grb2 to Ras, but not cells transformed by oncogenic Raf or cells that contain activating Ras mutations. Moreover, our results demonstrate that, in cells overexpressing receptor tyrosine kinases, such as the EGFR, Grb2 SH2 inhibitors induce expression of the cell cycle inhibitors p21(Waf1/Cip1/CAP1) and p27(Kip1) and reverse transformation.

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Cell Cycle Proteins*
  • Cell Line, Transformed
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclins / biosynthesis
  • Drug Design
  • GRB2 Adaptor Protein
  • Humans
  • Mice
  • Microtubule-Associated Proteins / biosynthesis
  • Molecular Sequence Data
  • Peptides / pharmacokinetics
  • Peptides / pharmacology*
  • Proteins / antagonists & inhibitors*
  • Proteins / physiology
  • Rats
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Recombinant Proteins
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*
  • ras Proteins / antagonists & inhibitors*
  • ras Proteins / physiology
  • src Homology Domains / drug effects*


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • CDKN1A protein, human
  • CGP 78850
  • CGP 85793
  • Cdkn1a protein, mouse
  • Cdkn1a protein, rat
  • Cdkn1b protein, mouse
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Grb2 protein, rat
  • Microtubule-Associated Proteins
  • Peptides
  • Proteins
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Receptor Protein-Tyrosine Kinases
  • ras Proteins