title: Macrocyclization in the design of a conformationally constrained Grb2 SH2 domain inhibitor.
abstract: Grubbs' olefin metathesis reaction was utilized to prepare a macrocyclic variant of a linear Grb2 SH2 domain antagonist in an attempt to induce a beta-bend conformation known to be required for high affinity binding. In extracellular Grb2 SH2 domain binding assays, the macrocyclic analogue exhibited an approximate 100-fold enhancement in binding potency relative to its linear counterpart. The macrocycle was not as effective in whole cell binding assays as would be expected based on its extracellular binding potency.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI at Frederick, National Institutes of Health, MD 21702, Frederick, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: J
authors.initials: J
authors.lastname: Voigt
authors.forename: J X
authors.initials: JX
authors.lastname: Wu
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.forename: T R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003500:Cyclization; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D051380:GRB2 Adaptor Protein; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D018909:src Homology Domains / Q000187:drug effects* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010455:Peptides; D011506:Proteins; D011955:Receptors, Drug; D014443:Tyrosine