Development of a phosphatase-stable phosphotyrosyl mimetic suitably protected for the synthesis of high-affinity Grb2 SH2 domain-binding ligands.
Synthesis of (2R)-2-carboxymethyl-3-(4-(phosphonomethyl)phenyl) proprionic acid (5) in tert-butyl-protected form (6) and its use for the preparation of a Grb2 SH2 domain-directed tripeptide (8a) is reported. In extracellular ELISA-based assays, 8a exhibits potent Grb2 SH2 domain binding affinity (IC(50)=8 nM). Against cultures of MDA-MB-453 breast cancer cells, which over-express erbB-2 tyrosine kinase, 8a is also antimitogenic at concentrations equivalent to those required to inhibit intracellular association of Grb2 protein with phosphorylated p185(erbB-2) protein (IC(50)=8 microM). Analogue 6 may be useful for the preparation of a variety of phosphatase-stable SH2 domain-directed ligands.
Wei
Chang-Qing
CQ
Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Li
Bihua
B
Guo
Ribo
R
Yang
Dajun
D
Burke
Terrence R
TR
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051380:GRB2 Adaptor Protein; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D018716:Molecular Mimicry; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry*; D019000:Phosphotyrosine / Q000737:chemistry*; D011506:Proteins / Q000187:drug effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; D007202:Indicators and Reagents; D008024:Ligands; D010744:Phosphoric Monoester Hydrolases; D019000:Phosphotyrosine; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C495948:GRB2 protein, human