title: Human alphavbeta3 integrin potency and specificity of TA138 and its DOTA conjugated form (89)Y-TA138.
abstract: The present study was undertaken to define the alphavbeta3-binding potency and specificity of TA138, a nonpeptide integrin antagonist, and its conjugated form, 89Y-TA138. Various integrin-specific binding and functional assays as well as cell-adhesion assays were used to determine the potency and integrin specificity for TA138 and 89Y-TA138. Both TA138 and 89Y-TA138 inhibited alphavbeta3-mediated [125I]echistatin binding to 293-beta3-transfected cells, with IC50 values of 0.046 and 0.059 microM, respectively, and IC50 values of 0.012 and 0.018 microM, respectively, in inhibiting an alphavbeta3 integrin-mediated 293-beta3-transfected cell adhesion to fibrinogen. TA138 inhibited human umbilical vein endothelial cell adhesion to fibrinogen, with an IC50 value of 0.052 +/- 0.006 microM. Both TA138 and 89Y-TA138 demonstrated a relatively high degree of specificity for human alphavbeta3 integrin as compared with other human integrins, including alphavbeta5, alphaIIbbeta3, and alpha5beta1 (IC50 > 10 microM). Both 89Y-TA138 and TA138 demonstrated comparable alphavbeta3 affinity and specificity as compared with other closely related human integrins such as alphavbeta5, alphaIIbbeta3, or alpha5beta1.
authors.affiliation: Albany College of Pharmacy, Albany, New York 12208-3492, USA. mousas@acp.edu
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Seema
authors.initials: S
authors.lastname: Mohamed
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005340:Fibrinogen / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D019096:Vitronectin / Q000502:physiology
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007202:Indicators and Reagents; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; C485703:TA 138; D019096:Vitronectin; C057986:echistatin; D005340:Fibrinogen