Tragex Pharma

Paris, France

Tragex Pharma

Paris, France
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Liu W.-Q.,University of Paris Descartes | Megale V.,University of Paris Descartes | Borriello L.,University of Paris Descartes | Leforban B.,University of Paris Descartes | And 15 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Neuropilins (NRPs) are VEGF-A165 co-receptors over-expressed in tumor cells, and considered as targets in angiogenic-related pathologies. We previously identified compound 1, the first non-peptidic antagonist of the VEGF-A165/NRP binding, which exhibits in vivo anti-angiogenic and anti-tumor activities. We report here the synthesis and biological evaluations of new antagonists structurally-related to compound 1. Among these molecules, 4a, 4c and 4d show cytotoxic effects on HUVEC and MDA-MB-31 cells, and antagonize VEGF-A165/NRP-1 binding. This study confirmed our key structure-activity relationships hypothesis and paved the way to compound 1 'hit to lead' optimization. © 2014 Elsevier Ltd. All rights reserved.


Goldwaser E.,The Saints | Goldwaser E.,University Pierre and Marie Curie | de Courcy B.,University Pierre and Marie Curie | Demange L.,The Saints | And 6 more authors.
Journal of Molecular Modeling | Year: 2014

We investigate the conformational properties of a potent inhibitor of neuropilin-1, a protein involved in cancer processes and macular degeneration. This inhibitor consists of four aromatic/conjugated fragments: a benzimidazole, a methylbenzene, a carboxythiourea, and a benzene-linker dioxane, and these fragments are all linked together by conjugated bonds. The calculations use the SIBFA polarizable molecular mechanics procedure. Prior to docking simulations, it is essential to ensure that variations in the ligand conformational energy upon rotations around its six main-chain torsional bonds are correctly represented (as compared to high-level ab initio quantum chemistry, QC). This is done in two successive calibration stages and one validation stage. In the latter, the minima identified following independent stepwise variations of each of the six main-chain torsion angles are used as starting points for energy minimization of all the torsion angles simultaneously. Single-point QC calculations of the minimized structures are then done to compare their relative energies ΔEconf to the SIBFA ones. We compare three different methods of deriving the multipoles and polarizabilities of the central, most critical moiety of the inhibitor: carboxythiourea (CTU). The representation that gives the best agreement with QC is the one that includes the effects of the mutual polarization energy Epol between the amide and thioamide moieties. This again highlights the critical role of this contribution. The implications and perspectives of these findings are discussed. © 2014, Springer-Verlag Berlin Heidelberg.


Jarray R.,University of Paris Descartes | Allain B.,University of Paris Descartes | Borriello L.,University of Paris Descartes | Biard D.,French Atomic Energy Commission | And 8 more authors.
Biochimie | Year: 2011

Using suppression subtractive hybridisation (SSH), we identified a hitherto unreported gene PHACTR-1 (Phosphatase Actin Regulating Protein-1) in Human Umbilical Vascular Endothelial Cells (HUVECs). PHACTR-1 is an actin and protein phosphatase 1 (PP1) binding protein which is reported to be highly expressed in brain and which controls PP1 activity and F-actin remodelling. We have also reported that its expression is dependent of Vascular Endothelial Growth Factor (VEGF-A 165). To study its function in endothelial cells, we used a siRNA strategy against PHACTR-1. PHACTR-1 siRNA-treated HUVECs showed a major impairment of tube formation and stabilisation. PHACTR-1 depletion triggered apoptosis through death receptors DR4, DR5 and FAS, which was reversed using death receptor siRNAs or with death receptor-dependent caspase-8 siRNA. Our findings suggest that PHACTR-1 is likely to be a key regulator of endothelial cell function properties. Because of its central role in the control of tube formation and endothelial cell survival, PHACTR-1 may represent a new target for the development of anti-angiogenic therapy. © 2011 Elsevier Masson SAS. All rights reserved.


Allain B.,University of Paris Descartes | Jarray R.,University of Paris Descartes | Borriello L.,University of Paris Descartes | Leforban B.,Tragex Pharma | And 10 more authors.
Cellular Signalling | Year: 2012

Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A 165-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We reported that Phactr-1 gene silencing inhibited tube formation in human umbilical endothelial cells (HUVECs) indicating a key role for Phactr-1 in tubulogenesis in vitro. In this study, we investigated the role of Phactr-1 in several cellular processes related to angiogenesis. We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect. We described a new interaction site of VEGF-A 165 to VEGF-R1 in peptides encoded by exons 7 and 8 of VEGF-A 165. The specific inhibition of VEGF-A 165 binding on NRP-1 and VEGF-R1 by ERTCRC and CDKPRR peptides decreased the Phactr-1 mRNA levels in HUVECs indicating that VEGF-A 165-dependent regulation of Phactr-1 expression required both NRP-1 and VEGF-R1 receptors. In addition, upon VEGFA 165-stimulation Phactr-1 promotes formation and maintenance of cellular tubes through NRP-1 and VEGFR1. Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process. © 2011 Elsevier Inc.


Borriello L.,University of Paris Descartes | Montes M.,French National Conservatory of Arts and Crafts | Lepelletier Y.,French Institute of Health and Medical Research | Lepelletier Y.,Paris-Sorbonne University | And 15 more authors.
Cancer Letters | Year: 2014

Neuropilin-1/-2 (+33 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-67low 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. © 2014 Elsevier Ireland Ltd.


Lecourt S.,French Institute of Health and Medical Research | Lecourt S.,Paris West University Nanterre La Défense | Lecourt S.,University Paris Diderot | Lepelletier Y.,University of Paris Descartes | And 16 more authors.
Stem Cells International | Year: 2012

In human skeletal muscle, myoblasts represent the main population of myogenic progenitors. We previously showed that, beside their myogenic differentiation capacities, myoblasts also differentiate towards osteogenic and chondrogenic lineages, some properties generally considered being hallmarks of mesenchymal stem cells (MSCs). MSCs are also characterized by their immunosuppressive potential, through cell-cell contacts and soluble factors, including prostaglandin E-2 (PGE-2), transforming growth factor-β1 (TGF-β1), interleukine-10, or indoleamine 2,3-dioxygenase. We and others also reported that Galectin-1 (Gal-1) and Semaphorin-3A (Sema-3A) were involved in MSCs-mediated immunosuppression. Here, we show that human myoblasts induce a significant and dose-dependant proliferation inhibition, independently of PGE-2 and TGF-β1. Our experiments revealed that myoblasts, in culture or in situ in human muscles, expressed and secreted Gal-1 and Sema-3A. Furthermore, myoblasts immunosuppressive functions were reverted by using blocking antibodies against Gal-1 or Sema-3A. Together, these results demonstrate an unsuspected immunosuppressive effect of myoblasts that may open new therapeutic perspectives. © 2012 Séverine Lecourt et al.


The present invention relates to a compound of general formula (I), and to a pharmaceutical composition comprising a compound of general formula (I) or esters or salts thereof, in association with at least one pharmaceutically acceptable vehicle; and to the use thereof for inhibiting the Neuropilin pathways in the treatment of cancer and of angiogenic diseases.


The present invention relates to a compound of general formula (I),for treating a Neuropilin-related disease, disorder or condition; and to a composition, a pharmaceutical composition and a medicament comprising the compound of general formula (I).


PubMed | Tragex Pharma, Paris-Sorbonne University, University Pierre and Marie Curie, University of Paris Descartes and French National Conservatory of Arts and Crafts
Type: Journal Article | Journal: Cancer letters | Year: 2014

Neuropilin-1/-2 (+33 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=34 M) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC50=0.60 M). 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=0.20 M). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.


The present invention relates to a pharmaceutical composition comprising a compound of general formula (I),- Z1 is S or O, preferably S;- -Z2- is -NR-, wherein R is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, preferably R^(a) is H; -N=; O; S; -CR=, wherein R is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO_(2), Cl, Br, I, F, preferably H; -CHR-, wherein R is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO_(2), Cl, Br, I, F, or -CH_(2)-; preferably -Z2- is -NH- or -N=;- each of R1 and R2 is independently H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO_(2), Cl, Br, I, F; preferably R1 and R2 together and with N and Z2 form an heterocycle eventually substituted, more preferably a substituted azocine, 3H-indole, indazole, 2-imidazoline, 2-pyrazoline, benzthiazole, purine, pyrimidine, pyridine, pyridazine, pyrazine, pyrazole, thiazole, isothiazole, oxazole, isoxazole, quinoline, isoquinoline, quinoxaline, quinazoline, 1-8-naphthyridine, perimidine, [1,10]-phenantroline, phthalazine, pteridine, triazole, triazine, furazan, 6H-1,2,5-thiadiazine, 1,3,4-thiadiazole, tetrazole, or a substituted imidazole and even more preferably a benzimidazole;- R5 is H, OH, C_(1-4) alkyl, C_(1-4) alkoxy, C_(1-4) alkenyl, C_(1-4) alkynyl, amine, preferably R5 is NH_(2), NO_(2), Cl, F, Br, I; more preferably R5 is H or CH_(3); even more preferably R5 is CH_(3);- each of R8 and R9 is independently, H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO_(2), Cl, Br, I, F; preferably R_(8) and R_(9) together form a cycle comprising 5 or 6 atoms, preferably an heterocycle comprising 5 or 6 atoms, more preferably a 1,3-dioxacyclopentene or a 1,4-dioxane; and- each of R3, R4, R6, R7, R10 and R11 is independently, H, OH, C_(1-4) alkyl, C_(1-4) alkoxy, C_(1-4) alkenyl, C_(1-4) alkynyl, amine, NO_(2), F, Cl, Br, I; preferably H, CH_(3), OCH_(3), OH, NH_(2), NO_(2), Cl, F, Br, I; more preferably is H or CH_(3); even more preferably is H,or esters or salts thereof; in association with at least one pharmaceutically acceptable vehicle; and to the use thereof for inhibiting the Neuropilin pathways in the treatment of cancer and of angiogenic diseases.

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