Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic

P Furet; C García-Echeverría; B Gay; J Schoepfer; M Zeller; J Rahuel

doi:10.1021/jm991013u

Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic

J Med Chem. 1999 Jul 1;42(13):2358-63. doi: 10.1021/jm991013u.

Authors

P Furet¹, C García-Echeverría, B Gay, J Schoepfer, M Zeller, J Rahuel

Affiliation

¹ Oncology Research Department, Novartis Pharma Inc., CH-4002 Basel, Switzerland. pascal.furet@pharma.novartis.com

PMID: 10395476
DOI: 10.1021/jm991013u

Abstract

Previous efforts in the search for molecules capable of blocking the associations between the activated tyrosine kinase growth factor receptors and the SH2 domain of Grb2 had resulted in the identification of 3-amino-Z-pTyr-Ac6c-Asn-NH2, a high-affinity and selective antagonist of this SH2 domain. In the present paper, we report the successful replacement of asparagine in this compound by a beta-amino acid mimetic, which brings us closer to our objective of identifying a Grb2-SH2 antagonist suitable for pharmacological investigations.

MeSH terms

Adaptor Proteins, Signal Transducing*
Asparagine / chemistry*
Carrier Proteins / antagonists & inhibitors*
Carrier Proteins / chemistry
Crystallography, X-Ray
Cyclohexanes / chemical synthesis*
Cyclohexanes / chemistry
Drug Design
ErbB Receptors / chemistry
Models, Molecular
Molecular Mimicry
Tyrosine / analogs & derivatives*
Tyrosine / chemical synthesis*
Tyrosine / chemistry
src Homology Domains*

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
Cyclohexanes
GRAP2 protein, human
Tyrosine
Asparagine
ErbB Receptors