Structure-based design of a non-peptidic antagonist of the SH2 domain of GRB2.
The structure-based design and synthesis of a completely non-peptidic, micromolar antagonist of the SH2 domain of Grb2 is presented. The compound mimics the two main pharmacophores of the natural ligand, the phenylphosphate of the phosphotyrosine residue and the beta-carboxamide of the X+2 asparagine, which are linked by a rigid aromatic spacer.
Caravatti
G
G
Novartis Pharmaceuticals, Inc., Therapeutic Area Oncology, Basel, Switzerland.
Rahuel
J
J
Gay
B
B
Furet
P
P
D048868:Adaptor Proteins, Signal Transducing; D003198:Computer Simulation; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D051380:GRB2 Adaptor Protein; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010710:Phosphates / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D018909:src Homology Domains / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D010455:Peptides; D010710:Phosphates; D010750:Phosphoproteins; D011506:Proteins; D011719:Pyrazines; D013844:Thiazoles