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Structure-Based Discovery Of A Small Anti-angiogenic Molecule Targeting Neuropilins With In Vivo Anti-tumor Activity | 13314
ISSN: 2167-065X
Clinical Pharmacology & Biopharmaceutics
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Angiogenesis, the formation of new vessels from a preexisting vasculature, plays a critical role in several diseases such as
cancer. To date, VEGF-A165, a spliced form of VEGFA (vascular endothelial growth factor), has been identified as one of the
key proangiogenic factors, and is strongly overexpressed in cancers. VEGF-A165 binds two structurally related receptor tyrosine
kinases, VEGFR-1 and VEGFR-2 and neuropilins (NRP-1 and NRP-2). These NRP co-receptors, lacking catalytic activity, form
complexes with VEGFR and VEGF-A165 and modulate their effect on the angiogenesis/tumoral signaling pathway. Moreover, NRP
over-expression enhances tumor growth and invasion and consequently is associated with a poor prognosis in various cancers. We
reasoned that the use of small molecules as antagonists of the protein-protein interaction between VEGF-A165 and NRPs might
be an innovative way to identify new anti-tumor drugs. Here we report our use of
in silico/in vitro/in vivo
screening to discover
an original lead. We showed that this molecule antagonizes VEGF-A binding to NRP-1 and NRP-2. In a tubulogenesis assay in
HUVECs, we found that our lead compound was involved in the inhibition of tubule formation underlying its involvement in
angiogenesis. Furthermore, in vivo experiments on NOG-xenografted mice showed a significant antitumor effect and significantly
increased survival.
Biography
Luc Demange completed his Ph.D. in 2001 under the guidance of Dr. C. Dugave on cis-trans isomerization catalyzed by hCyp-18. Then, he moved
to Sherbrooke (Canada) and worked with Prof. P. Deslongchamps on steroid synthesis. In 2004-2006, he studied with Prof. J. Martinez ghrelin
secretagogs. He joined in 2006 Prof. C. Garbay unit in Paris-Descartes University. His research is currently based on the design and evaluation of
protein-protein interaction inhibitors (applied to angiogenesis and AIDS); he also investigated new organic reactions to identify CDKs inhibitors. Luc
Demange published more than 25 papers and patents; he was awarded by the French Therapeutic Chemical Society (SCT, 2007).
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