Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic.
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.
Oncology Research Department, Novartis Pharma Inc., CH-4002 Basel, Switzerland. pascal.furet@pharma.novartis.com
P
P
Furet
C
C
García-Echeverría
B
B
Gay
J
J
Schoepfer
M
M
Zeller
J
J
Rahuel
D048868:Adaptor Proteins, Signal Transducing; D001216:Asparagine / Q000737:chemistry*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D066246:ErbB Receptors / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003510:Cyclohexanes; C409587:GRAP2 protein, human; D014443:Tyrosine; D001216:Asparagine; D066246:ErbB Receptors