A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras.
The efficacy of anti-angiogenic therapies on cancer patients is limited by the emergence of drug resistance, urging the search for second-generation drugs. In this study, we screened an academic chemical library (DCM, University of Grenoble-Alpes) and identified a leader molecule, COB223, that inhibits endothelial cell migration and proliferation. It inhibits also Lewis lung carcinoma (LLC/2) cell proliferation whereas it does not affect fibroblast proliferation. The anti-angiogenic activity of COB223 was confirmed using several in vitro and in vivo assays. In a mouse LLC/2 tumor model, ip administration of doses as low as 4 mg/kg COB223 efficiently reduced the tumor growth rate. We observed that COB223 inhibits endothelial cell ERK1/2 phosphorylation induced by VEGF, FGF-2 or serum and that it acts downstream of PKC and upstream of Ras. This molecule represents a novel anti-angiogenic and anti-tumorigenic agent with an original mechanism of action that deserves further development as an anti-cancer drug.
Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1036, Biology of Cancer and Infection, Grenoble, F-38054, France.|Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Commissariat à l'Energie Atomique (CEA), DSV/iRTSV, Grenoble, F-38054, France.
Agnès
A
Desroches-Castan
Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1036, Biology of Cancer and Infection, Grenoble, F-38054, France.|Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Commissariat à l'Energie Atomique (CEA), DSV/iRTSV, Grenoble, F-38054, France.|Janssen, Pharmaceutical Companies of Johnson and Johnson, Issy-les-Moulineaux, F-92130, France.
Delphine
D
Quélard
Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Centre National de la Recherche Scientifique (CNRS), UMR 5063, Department of Molecular Pharmacochemistry, Grenoble, F-38041, France.
Martine
M
Demeunynck
Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Centre National de la Recherche Scientifique (CNRS), UMR 5250, Department of Molecular Chemistry, Grenoble, F-38041, France.
Jean-François
JF
Constant
Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Centre National de la Recherche Scientifique (CNRS), UMR 5250, Department of Molecular Chemistry, Grenoble, F-38041, France.
Chongling
C
Dong
Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 823, Albert Bonniot Research Center, La Tronche, F-38700, France.
Michelle
M
Keramidas
Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 823, Albert Bonniot Research Center, La Tronche, F-38700, France.
Jean-Luc
JL
Coll
Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Commissariat à l'Energie Atomique (CEA), DSV/iRTSV, Grenoble, F-38054, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1038, Large Scale Biology, Grenoble, F-38054, France.
Caroline
C
Barette
Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Commissariat à l'Energie Atomique (CEA), DSV/iRTSV, Grenoble, F-38054, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 823, Albert Bonniot Research Center, La Tronche, F-38700, France.
Laurence
L
Lafanechère
Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1036, Biology of Cancer and Infection, Grenoble, F-38054, France.|Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France.|Commissariat à l'Energie Atomique (CEA), DSV/iRTSV, Grenoble, F-38054, France.
Jean-Jacques
JJ
Feige
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; C000604218:COB223; D002219:Carbamates; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D018631:ras Proteins
VEGF signaling; angiogenesis; chemical library; drug development