Structure-based design and synthesis of phosphinate isosteres of phosphotyrosine for incorporation in Grb2-SH2 domain inhibitors. Part 1

P Furet; G Caravatti; A A Denholm; A Faessler; H Fretz; C García-Echeverría; B Gay; E Irving; N J Press; J Rahuel; J Schoepfer; C V Walker

doi:10.1016/s0960-894x(00)00475-3

Structure-based design and synthesis of phosphinate isosteres of phosphotyrosine for incorporation in Grb2-SH2 domain inhibitors. Part 1

Bioorg Med Chem Lett. 2000 Oct 16;10(20):2337-41. doi: 10.1016/s0960-894x(00)00475-3.

Authors

P Furet¹, G Caravatti, A A Denholm, A Faessler, H Fretz, C García-Echeverría, B Gay, E Irving, N J Press, J Rahuel, J Schoepfer, C V Walker

Affiliation

¹ Novartis Pharmaceuticals, Inc., Therapeutic Area Oncology, Basel, Switzerland. pascal.furet@pharma.novartis.com

PMID: 11055351
DOI: 10.1016/s0960-894x(00)00475-3

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.

MeSH terms

Adaptor Proteins, Signal Transducing*
Binding Sites
Crystallography, X-Ray
Drug Design
GRB2 Adaptor Protein
Hydrogen Bonding
Ligands
Oligopeptides / chemical synthesis*
Oligopeptides / chemistry
Oligopeptides / pharmacology
Phosphinic Acids / chemical synthesis*
Phosphinic Acids / chemistry
Phosphinic Acids / pharmacology
Phosphotyrosine / analogs & derivatives*
Phosphotyrosine / chemical synthesis*
Phosphotyrosine / chemistry
Proteins / antagonists & inhibitors*
Proteins / chemistry*
Structure-Activity Relationship
src Homology Domains

Substances

Adaptor Proteins, Signal Transducing
GRB2 Adaptor Protein
Ligands
Oligopeptides
Phosphinic Acids
Proteins
Phosphotyrosine