Alphavbeta3 integrin binding affinity and specificity of SM256 in various species.
This study was undertaken to define the alphavbeta3 binding affinity and specificity of the low-molecular-weight nonpeptide integrin antagonist, SM256. SM256 demonstrated high potency (IC50, 0.057+/-0.030 nM) in inhibiting vitronectin binding to purified human alphavbeta3 receptors. Additionally, SM256 inhibited alphavbeta3-mediated human umbilical vein endothelial cell (HUVEC) or 293/beta3 (beta3-transfected cell line) adhesion to fibrinogen with IC50 values of 0.0054+/-0.0058 and 0.0023+/-0.0012 microM, respectively. SM256 demonstrated a relatively high degree of specificity for human alphavbeta3-mediated functions as compared with other human integrins including alphavbeta5 (IC50, 0.92+/-0.69 microM), alphaIIbbeta3 (IC50, 0.72+/-0.07 microM), alpha4/beta1 (IC50, >100 microM) and alpha5/beta1 (IC50, 2.3+/-2.1 microM). SM256 demonstrated different degree of species specificity in blocking alphavbeta3-mediated cellular adhesion with relatively higher affinity to dog (IC50, 0.005+/-0.002 microM), rabbit (IC50, 0.021+/-0.01 microM), mouse (IC50, 0.035+/-0.01 microM), and pig (IC50, 0.41+/-0.24 microM) endothelial or smooth-muscle cell alphavbeta3-mediated adhesion. Additionally, SM256 demonstrated high degree of alphavbeta3 specificity as compared with alphavbeta5, alpha5beta1, or alphaIIbbeta3-mediated binding in these species. SM256 is a potent alphavbeta3, antagonist with high affinity and specificity for alphavbeta3-mediated functions. Additionally, a comparable alphavbeta3 affinity for SM256 was demonstrated with endothelial cells obtained from various species (dog, mouse, rabbit, and pig) as compared with that from human.
Mousa
S A
SA
DuPont Pharmaceuticals Co., Wilmington, Delaware 19880-0400, USA.
Lorelli
W
W
Mohamed
S
S
Batt
D G
DG
Jadhav
P K
PK
Reilly
T M
TM
D000818:Animals; D001667:Binding, Competitive; D019921:Biotinylation; D004285:Dogs; D006801:Humans; D007191:Indazoles / Q000378:metabolism*; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D011817:Rabbits; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013449:Sulfonamides / Q000378:metabolism*; D013552:Swine; D019096:Vitronectin / Q000378:metabolism
D007191:Indazoles; D016023:Integrins; D019030:Receptors, Vitronectin; C119284:SM 256; D013449:Sulfonamides; D019096:Vitronectin