Structure-based design and synthesis of phosphinate isosteres of phosphotyrosine for incorporation in Grb2-SH2 domain inhibitors. Part 1.
Based on X-ray crystal structure information, mono charged phosphinate isosteres of phosphotyrosine have been designed and incorporated in a short inhibitory peptide sequence of the Grb2-SH2 domain. The resulting compounds, by exploiting additional interactions, inhibit binding to the Grb2-SH2 domain as potently as the corresponding doubly charged (phosphonomethyl)phenylalanine analogue.
Furet
P
P
Novartis Pharmaceuticals, Inc., Therapeutic Area Oncology, Basel, Switzerland. pascal.furet@pharma.novartis.com
Caravatti
G
G
Denholm
A A
AA
Faessler
A
A
Fretz
H
H
García-Echeverría
C
C
Gay
B
B
Irving
E
E
Press
N J
NJ
Rahuel
J
J
Schoepfer
J
J
Walker
C V
CV
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D051380:GRB2 Adaptor Protein; D006860:Hydrogen Bonding; D008024:Ligands; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019000:Phosphotyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D008024:Ligands; D009842:Oligopeptides; D010721:Phosphinic Acids; D011506:Proteins; D019000:Phosphotyrosine