Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist.
New blood vessel formation is essential for tumor growth and metastatic spread. Integrins alpha(v)beta3 and alpha(v)beta5 are arginine-glycine-aspartic acid-dependent adhesion receptors that play a critical role in angiogenesis. Hence, selective dual alpha(v)beta3 and alpha(v)beta5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. Here, an arginine-glycine-aspartic acid-based peptidomimetic library was screened to identify alpha(v)beta3 antagonists. Selected compounds were then modified to generate potent and selective dual inhibitors of alpha(v)beta3 and alpha(v)beta5 receptors. One of these compounds, SCH 221153, inhibited the binding of echistatin to alpha(v)beta3 (IC50 = 3.2 nM) and alpha(v)beta5 (IC50 = 1.7 nM) with similar potency. Its IC50 values for related alpha(IIb)beta3 and alpha5beta1 receptors were 1294 nM and 421 nM, respectively, indicating that SCH 221153 is highly selective for alpha(v)beta3 and alpha(v)beta5 receptors. In cell-based assays, SCH 221153 inhibited the binding of echistatin to alpha(v)beta3- and alpha(v)beta5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and fibroblast growth factor 2 (FGF2). SCH 221153, but not the inactive analogue SCH 216687, was effective in inhibiting FGF2 and vascular endothelial growth factor-induced endothelial cell proliferation in vitro with an IC50 equal to 3-10 microM. Angiogenesis induced by FGF2 in the chick chorioallantoic membrane assay was also inhibited by SCH 221153. Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or s.c. injection of human melanoma LOX cells in severe combined immunodeficient mice.
Kumar
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CC
Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. chandra.kumar@spcorp.com
Malkowski
M
M
Yin
Z
Z
Tanghetti
E
E
Yaremko
B
B
Nechuta
T
T
Varner
J
J
Liu
M
M
Smith
E M
EM
Neustadt
B
B
Presta
M
M
Armstrong
L
L
D000482:Allantois / Q000098:blood supply; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019096:Vitronectin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D006131:Growth Inhibitors; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009842:Oligopeptides; D010455:Peptides; D019030:Receptors, Vitronectin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019096:Vitronectin; C064660:integrin alphaVbeta5; D016222:Fibroblast Growth Factor 2; C057986:echistatin; C047981:arginyl-glycyl-aspartic acid