Structure-based design of peptidomimetic ligands of the Grb2-SH2 domain.
We have designed and synthesized a (3-aminomethyl-phenyl)-urea scaffold to mimic the X+1-Asn part of the minimal phosphopeptide sequence, Ac-pTyr-X+1-Asn-NH2, recognized by the Grb2-SH2 domain. The resulting compounds show the same degree of affinity as their peptide counterparts for the Grb2-SH2 domain. This is the first example reported to date of ligands of the Grb2-SH2 domain with substantially reduced peptidic character.
Schoepfer
J
J
Novartis Pharma Inc., Oncology Research Department, Basle, Switzerland.
Gay
B
B
Caravatti
G
G
Garcia-Echeverria
C
C
Fretz
H
H
Rahuel
J
J
Furet
P
P
D048868:Adaptor Proteins, Signal Transducing; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D051380:GRB2 Adaptor Protein; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D010748:Phosphopeptides / Q000737:chemistry* / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D008024:Ligands; D010748:Phosphopeptides; D011506:Proteins; D066246:ErbB Receptors