title: Structure-based design and synthesis of phosphinate isosteres of phosphotyrosine for incorporation in Grb2-SH2 domain inhibitors. Part 1.
abstract: 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.
authors.affiliation: Novartis Pharmaceuticals, Inc., Therapeutic Area Oncology, Basel, Switzerland. pascal.furet@pharma.novartis.com
authors.forename: P
authors.initials: P
authors.lastname: Furet
authors.forename: G
authors.initials: G
authors.lastname: Caravatti
authors.forename: A A
authors.initials: AA
authors.lastname: Denholm
authors.forename: A
authors.initials: A
authors.lastname: Faessler
authors.forename: H
authors.initials: H
authors.lastname: Fretz
authors.forename: C
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: B
authors.initials: B
authors.lastname: Gay
authors.forename: E
authors.initials: E
authors.lastname: Irving
authors.forename: N J
authors.initials: NJ
authors.lastname: Press
authors.forename: J
authors.initials: J
authors.lastname: Rahuel
authors.forename: J
authors.initials: J
authors.lastname: Schoepfer
authors.forename: C V
authors.initials: CV
authors.lastname: Walker
mesh_terms: 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
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D008024:Ligands; D009842:Oligopeptides; D010721:Phosphinic Acids; D011506:Proteins; D019000:Phosphotyrosine