INHIBITION OF ANGIOGENESIS AND TUMOR GROWTH BY SCH221153, A DUAL aVb3 AND aVb5 INTEGRIN RECEPTOR ANTAGONIST
 

 
 
Chandra Kumar, C**., Malkowski, M*, Yin, Z*, Tanghetti, E$., Yaremko, B*., Nechuta, T#., Varner, J+., Liu, Ming*., Smith, E. M#., Neustadt, B#., Presta, M$., and Armstrong, L*

 
*Dept. of Tumor Biology, and  # Dept. of Medicinal Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., $ Dept. of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, 25123 Brescia, Italy, + U. of California at San Diego, San Diego, CA 

 

 
 

Chemical structure
of SCH 221153
 
 


 
 

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    ABSTRACT
 
New blood vessel formation is essential for tumor growth and metastatic spread.  Integrins aVb3 and aVb5 are arginine-glycine-aspartic acid (RGD)-dependent adhesion receptors that play a critical role in angiogenesis.  Hence, selective dual aVb3 and aVb5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. 

Here, an RGD-based peptidomimetic library was screened to identify aVb3 antagonists.  Selected compounds were then modified to generate potent and selective dual inhibitors of aVb3 and aVb5 receptors.  One of these compounds, SCH 221153, inhibited the binding of echistatin to aVb3 (IC50 = 3.2 nM) and aVb5 (IC50 = 1.7 nM) with similar potency.  Its IC50 values for related aIIbb3  and a5b1 receptors were 1294 nM and 421 nM, respectively, indicating that SCH 221153 is highly selective for aVb3 and aVb5 receptors. 

In cell-based assays, SCH 221153 inhibited the binding of echistatin to aVb3- and aVb5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and FGF2.  SCH 221153, but not the inactive analog SCH 216687, was effective in inhibiting FGF2 and VEGF-induced endothelial cell proliferation in vitro with an IC50 equal to 3-10 mM. 

Angiogenesis induced by FGF2 in the chick chorioallantoic membrane (CAM) assay was also inhibited by SCH 221153.  Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or subcutaneous injection of human melanoma LOX cells in SCID mice.

Cancer Res., 61: 2232-2238 (2001)


 

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AIRC: Special Project Angiogenesis