Published in
Elsevier, Cancer Letters, 2(349), p. 120-127
DOI: 10.1016/j.canlet.2014.04.004
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Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model
,
Yves Lepelletier,
Bertrand Leforban,
Wang-Qing Liu,
Luc Demange,
Brigitte Delhomme,
Serena Pavoni,
Rafika Jarray,
Jean Luc Boucher,
Sylvie Dufour,
Olivier Hermine ,
Christiane Garbay,
Reda Hadj-Slimane
and other authors.
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Abstract
Neuropilin-1/-2 (NRPs), VEGF-A165 co-receptors, are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A165/NRPs protein-protein interaction antagonist (IC50=34μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC50=0.60μM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67(low) expression and apoptosis. Furthermore, CD31(+)/CD34(+) vessels are reduced in accordance with HUVEC-tube formation inhibition (IC50=0.20μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.