title: Identification of a nonpeptide ligand that releases bioactive insulin-like growth factor-I from its binding protein complex.
abstract: Insulin-like growth factor-I (IGF-I) has both metabolic and mitogenic activities mediated through interaction with the type 1 IGF receptor. The circulation of IGF-I in blood and interstitial fluid is not free but bound mostly to a family of six high affinity IGF-binding proteins, which form stable complexes with IGF and neutralize its bioactivity. Therefore, displacement of this large pool of endogenous IGF from the binding proteins could elevate "free" IGF levels to elicit beneficial effects in diabetes and other IGF-responsive diseases comparable with those produced by administration of exogenous IGF-I. We report here the identification of a nonpeptide ligand NBI-31772, which displaces IGF-I from all six IGF-binding proteins at low nanomolar concentrations from screening of the in-house chemical libraries. Furthermore, the released free IGF-I was shown to be biologically active in an in vitro bioassay. Thus, NBI-31772 could serve as a valuable lead molecule for the design of novel therapeutics to treat diabetes and other IGF-responsive diseases.
authors.affiliation: Department of Peptide Chemistry, Neurocrine Biosciences, Inc., San Diego, California 92121, USA.
authors.forename: X J
authors.initials: XJ
authors.lastname: Liu
authors.forename: Q
authors.initials: Q
authors.lastname: Xie
authors.forename: Y F
authors.initials: YF
authors.lastname: Zhu
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Ling
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000187:drug effects* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D011869:Radioligand Assay; D011994:Recombinant Proteins / Q000378:metabolism; D018411:Spodoptera; D014162:Transfection
chemical_list: D002396:Catechols; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018974:Insulin-Like Growth Factor Binding Protein 4; D018975:Insulin-Like Growth Factor Binding Protein 5; D018976:Insulin-Like Growth Factor Binding Protein 6; D018969:Insulin-Like Growth Factor Binding Proteins; D007457:Iodine Radioisotopes; D007546:Isoquinolines; D008024:Ligands; C436731:NBI 31772; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I