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Identification of new aminoacid amides containing the imidazo[2,1-b] benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling

Identifieur interne : 000102 ( PascalFrancis/Corpus ); précédent : 000101; suivant : 000103

Identification of new aminoacid amides containing the imidazo[2,1-b] benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling

Auteurs : Alessandro Furlan ; Francesco Colombo ; Andrea Kover ; Nathalie Issaly ; Cristina Tintori ; Lucilla Angeli ; Vincent Leroux ; Sebastien Letard ; Mercedes Amat ; Yasmine Asses ; Bernard Maigret ; Patrice Dubreuil ; Maurizio Botta ; Rosanna Dono ; Joan Bosch ; Oreste Piccolo ; Daniele Passarella ; Flavio Maina

Source :

RBID : Pascal:12-0387743

Descripteurs français

English descriptors

Abstract

The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

pA  
A01 01  1    @0 0223-5234
A02 01      @0 EJMCA5
A03   1    @0 Eur. j. med. chem.
A05       @2 47
A08 01  1  ENG  @1 Identification of new aminoacid amides containing the imidazo[2,1-b] benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling
A11 01  1    @1 FURLAN (Alessandro)
A11 02  1    @1 COLOMBO (Francesco)
A11 03  1    @1 KOVER (Andrea)
A11 04  1    @1 ISSALY (Nathalie)
A11 05  1    @1 TINTORI (Cristina)
A11 06  1    @1 ANGELI (Lucilla)
A11 07  1    @1 LEROUX (Vincent)
A11 08  1    @1 LETARD (Sebastien)
A11 09  1    @1 AMAT (Mercedes)
A11 10  1    @1 ASSES (Yasmine)
A11 11  1    @1 MAIGRET (Bernard)
A11 12  1    @1 DUBREUIL (Patrice)
A11 13  1    @1 BOTTA (Maurizio)
A11 14  1    @1 DONO (Rosanna)
A11 15  1    @1 BOSCH (Joan)
A11 16  1    @1 PICCOLO (Oreste)
A11 17  1    @1 PASSARELLA (Daniele)
A11 18  1    @1 MAINA (Flavio)
A14 01      @1 Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907 @2 13288 Marseille @3 FRA @Z 1 aut. @Z 4 aut. @Z 14 aut. @Z 18 aut.
A14 02      @1 Dipartimento di Chimica Organica e Indusriale, Università degli Studi di Milano, Via Venezian 21 @2 20133 Milano @3 ITA @Z 2 aut. @Z 17 aut.
A14 03      @1 Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona @2 08028 Barcelona @3 ESP @Z 3 aut. @Z 9 aut. @Z 15 aut.
A14 04      @1 Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2 @2 53100 Siena @3 ITA @Z 5 aut. @Z 6 aut. @Z 13 aut.
A14 05      @1 Nancy Université, LORIA-UMR 7503, Equipe projet Orpailleur, Campus scientifique, BP 239 @2 54506 Vandœuvre-lès-Nancy @3 FRA @Z 7 aut. @Z 10 aut. @Z 11 aut.
A14 06      @1 University of Oslo, Chemistry Department, P.O. Box 1033 Blindern @2 0315 Oslo @3 NOR @Z 7 aut.
A14 07      @1 Centre de Recherche en Cancérologie de Marseille -U891 INSERM, Institut Paoli-Calmettes, Université de la Méditerranée 27, boulevard Lei Roure BP 30059 @2 13273 Marseille @3 FRA @Z 8 aut. @Z 12 aut.
A14 08      @1 Studio di consulenza scientifica, Via Bornò 5 @2 23896 Sirtori (LC @3 ITA @Z 16 aut.
A20       @1 239-254
A21       @1 2012
A23 01      @0 ENG
A43 01      @1 INIST @2 12640 @5 354000508861270270
A44       @0 0000 @1 © 2012 INIST-CNRS. All rights reserved.
A45       @0 50 ref.
A47 01  1    @0 12-0387743
A60       @1 P
A61       @0 A
A64 01  1    @0 European journal of medicinal chemistry
A66 01      @0 GBR
C01 01    ENG  @0 The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting.
C02 01  X    @0 002B02R01
C03 01  X  FRE  @0 Aminoamide @5 01
C03 01  X  ENG  @0 Aminoamide @5 01
C03 01  X  SPA  @0 Aminoamida @5 01
C03 02  X  FRE  @0 Gène onc @5 02
C03 02  X  ENG  @0 Onc gene @5 02
C03 02  X  SPA  @0 Gen onc @5 02
C03 03  X  FRE  @0 Inhibiteur @5 03
C03 03  X  ENG  @0 Inhibitor @5 03
C03 03  X  SPA  @0 Inhibidor @5 03
C03 04  X  FRE  @0 Carcinogenèse @5 04
C03 04  X  ENG  @0 Carcinogenesis @5 04
C03 04  X  SPA  @0 Carcinogénesis @5 04
C03 05  X  FRE  @0 Mode liaison @5 05
C03 05  X  ENG  @0 Binding mode @5 05
C03 05  X  SPA  @0 Modo de enlace @5 05
C03 06  X  FRE  @0 Anticancéreux @5 06
C03 06  X  ENG  @0 Antineoplastic agent @5 06
C03 06  X  SPA  @0 Anticanceroso @5 06
C03 07  X  FRE  @0 Activité biologique @5 07
C03 07  X  ENG  @0 Biological activity @5 07
C03 07  X  SPA  @0 Actividad biológica @5 07
C03 08  X  FRE  @0 Modèle moléculaire @5 08
C03 08  X  ENG  @0 Molecular model @5 08
C03 08  X  SPA  @0 Modelo molecular @5 08
C03 09  X  FRE  @0 Synthèse chimique @5 09
C03 09  X  ENG  @0 Chemical synthesis @5 09
C03 09  X  SPA  @0 Síntesis química @5 09
C03 10  X  FRE  @0 Fluor Composé organique @2 NC @2 FX @2 NA @5 10
C03 10  X  ENG  @0 Fluorine Organic compounds @2 NC @2 FX @2 NA @5 10
C03 10  X  SPA  @0 Fluor Compuesto orgánico @2 NC @2 FX @2 NA @5 10
C03 11  X  FRE  @0 Souris @5 11
C03 11  X  ENG  @0 Mouse @5 11
C03 11  X  SPA  @0 Ratón @5 11
C03 12  X  FRE  @0 Transduction signal @5 32
C03 12  X  ENG  @0 Signal transduction @5 32
C03 12  X  SPA  @0 Transducción señal @5 32
C03 13  X  FRE  @0 Transferases @2 FE @5 33
C03 13  X  ENG  @0 Transferases @2 FE @5 33
C03 13  X  SPA  @0 Transferases @2 FE @5 33
C03 14  X  FRE  @0 Modélisation @5 34
C03 14  X  ENG  @0 Modeling @5 34
C03 14  X  SPA  @0 Modelización @5 34
C03 15  X  FRE  @0 Animal @5 35
C03 15  X  ENG  @0 Animal @5 35
C03 15  X  SPA  @0 Animal @5 35
C03 16  X  FRE  @0 Imidazo[2,1-b]benzothiazole dérivé @4 INC @5 76
C03 17  X  FRE  @0 Phénylalaninamide(Nα-[3,5-bis(trifluorométhyl)hénylacétyl]) dérivé @2 NK @4 INC @5 77
C03 18  X  FRE  @0 Imidazobenzothiazole @4 INC @5 91
C03 19  X  FRE  @0 Receptor protein-tyrosine kinase @4 CD @5 96
C03 19  X  ENG  @0 Receptor protein-tyrosine kinase @4 CD @5 96
C03 19  X  SPA  @0 Receptor protein-tyrosine kinase @4 CD @5 96
C07 01  X  FRE  @0 Rodentia @2 NS
C07 01  X  ENG  @0 Rodentia @2 NS
C07 01  X  SPA  @0 Rodentia @2 NS
C07 02  X  FRE  @0 Mammalia @2 NS
C07 02  X  ENG  @0 Mammalia @2 NS
C07 02  X  SPA  @0 Mammalia @2 NS
C07 03  X  FRE  @0 Vertebrata @2 NS
C07 03  X  ENG  @0 Vertebrata @2 NS
C07 03  X  SPA  @0 Vertebrata @2 NS
C07 04  X  FRE  @0 Enzyme @2 FE
C07 04  X  ENG  @0 Enzyme @2 FE
C07 04  X  SPA  @0 Enzima @2 FE
N21       @1 303

Format Inist (serveur)

NO : PASCAL 12-0387743 INIST
ET : Identification of new aminoacid amides containing the imidazo[2,1-b] benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling
AU : FURLAN (Alessandro); COLOMBO (Francesco); KOVER (Andrea); ISSALY (Nathalie); TINTORI (Cristina); ANGELI (Lucilla); LEROUX (Vincent); LETARD (Sebastien); AMAT (Mercedes); ASSES (Yasmine); MAIGRET (Bernard); DUBREUIL (Patrice); BOTTA (Maurizio); DONO (Rosanna); BOSCH (Joan); PICCOLO (Oreste); PASSARELLA (Daniele); MAINA (Flavio)
AF : Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907/13288 Marseille/France (1 aut., 4 aut., 14 aut., 18 aut.); Dipartimento di Chimica Organica e Indusriale, Università degli Studi di Milano, Via Venezian 21/20133 Milano/Italie (2 aut., 17 aut.); Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona/08028 Barcelona/Espagne (3 aut., 9 aut., 15 aut.); Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2/53100 Siena/Italie (5 aut., 6 aut., 13 aut.); Nancy Université, LORIA-UMR 7503, Equipe projet Orpailleur, Campus scientifique, BP 239/54506 Vandœuvre-lès-Nancy/France (7 aut., 10 aut., 11 aut.); University of Oslo, Chemistry Department, P.O. Box 1033 Blindern/0315 Oslo/Norvège (7 aut.); Centre de Recherche en Cancérologie de Marseille -U891 INSERM, Institut Paoli-Calmettes, Université de la Méditerranée 27, boulevard Lei Roure BP 30059/13273 Marseille/France (8 aut., 12 aut.); Studio di consulenza scientifica, Via Bornò 5/23896 Sirtori (LC/Italie (16 aut.)
DT : Publication en série; Niveau analytique
SO : European journal of medicinal chemistry; ISSN 0223-5234; Coden EJMCA5; Royaume-Uni; Da. 2012; Vol. 47; Pp. 239-254; Bibl. 50 ref.
LA : Anglais
EA : The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting.
CC : 002B02R01
FD : Aminoamide; Gène onc; Inhibiteur; Carcinogenèse; Mode liaison; Anticancéreux; Activité biologique; Modèle moléculaire; Synthèse chimique; Fluor Composé organique; Souris; Transduction signal; Transferases; Modélisation; Animal; Imidazo[2,1-b]benzothiazole dérivé; Phénylalaninamide(Nα-[3,5-bis(tri fluorométhyl)hénylacétyl]) dérivé; Imidazobenzothiazole; Receptor protein-tyrosine kinase
FG : Rodentia; Mammalia; Vertebrata; Enzyme
ED : Aminoamide; Onc gene; Inhibitor; Carcinogenesis; Binding mode; Antineoplastic agent; Biological activity; Molecular model; Chemical synthesis; Fluorine Organic compounds; Mouse; Signal transduction; Transferases; Modeling; Animal; Receptor protein-tyrosine kinase
EG : Rodentia; Mammalia; Vertebrata; Enzyme
SD : Aminoamida; Gen onc; Inhibidor; Carcinogénesis; Modo de enlace; Anticanceroso; Actividad biológica; Modelo molecular; Síntesis química; Fluor Compuesto orgánico; Ratón; Transducción señal; Transferases; Modelización; Animal; Receptor protein-tyrosine kinase
LO : INIST-12640.354000508861270270
ID : 12-0387743

Links to Exploration step

Pascal:12-0387743

Le document en format XML

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<name sortKey="Letard, Sebastien" sort="Letard, Sebastien" uniqKey="Letard S" first="Sebastien" last="Letard">Sebastien Letard</name>
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<name sortKey="Amat, Mercedes" sort="Amat, Mercedes" uniqKey="Amat M" first="Mercedes" last="Amat">Mercedes Amat</name>
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<name sortKey="Asses, Yasmine" sort="Asses, Yasmine" uniqKey="Asses Y" first="Yasmine" last="Asses">Yasmine Asses</name>
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<name sortKey="Maigret, Bernard" sort="Maigret, Bernard" uniqKey="Maigret B" first="Bernard" last="Maigret">Bernard Maigret</name>
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<name sortKey="Dubreuil, Patrice" sort="Dubreuil, Patrice" uniqKey="Dubreuil P" first="Patrice" last="Dubreuil">Patrice Dubreuil</name>
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<name sortKey="Botta, Maurizio" sort="Botta, Maurizio" uniqKey="Botta M" first="Maurizio" last="Botta">Maurizio Botta</name>
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<name sortKey="Dono, Rosanna" sort="Dono, Rosanna" uniqKey="Dono R" first="Rosanna" last="Dono">Rosanna Dono</name>
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<s1>Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907</s1>
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<name sortKey="Bosch, Joan" sort="Bosch, Joan" uniqKey="Bosch J" first="Joan" last="Bosch">Joan Bosch</name>
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<s1>Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona</s1>
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<name sortKey="Piccolo, Oreste" sort="Piccolo, Oreste" uniqKey="Piccolo O" first="Oreste" last="Piccolo">Oreste Piccolo</name>
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<s1>Studio di consulenza scientifica, Via Bornò 5</s1>
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<div type="abstract" xml:lang="en">The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting.</div>
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<s0>Inhibitor</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="SPA">
<s0>Inhibidor</s0>
<s5>03</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE">
<s0>Carcinogenèse</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG">
<s0>Carcinogenesis</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA">
<s0>Carcinogénesis</s0>
<s5>04</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE">
<s0>Mode liaison</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG">
<s0>Binding mode</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA">
<s0>Modo de enlace</s0>
<s5>05</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE">
<s0>Anticancéreux</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG">
<s0>Antineoplastic agent</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA">
<s0>Anticanceroso</s0>
<s5>06</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE">
<s0>Activité biologique</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG">
<s0>Biological activity</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="SPA">
<s0>Actividad biológica</s0>
<s5>07</s5>
</fC03>
<fC03 i1="08" i2="X" l="FRE">
<s0>Modèle moléculaire</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="ENG">
<s0>Molecular model</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA">
<s0>Modelo molecular</s0>
<s5>08</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE">
<s0>Synthèse chimique</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="ENG">
<s0>Chemical synthesis</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="SPA">
<s0>Síntesis química</s0>
<s5>09</s5>
</fC03>
<fC03 i1="10" i2="X" l="FRE">
<s0>Fluor Composé organique</s0>
<s2>NC</s2>
<s2>FX</s2>
<s2>NA</s2>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="ENG">
<s0>Fluorine Organic compounds</s0>
<s2>NC</s2>
<s2>FX</s2>
<s2>NA</s2>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA">
<s0>Fluor Compuesto orgánico</s0>
<s2>NC</s2>
<s2>FX</s2>
<s2>NA</s2>
<s5>10</s5>
</fC03>
<fC03 i1="11" i2="X" l="FRE">
<s0>Souris</s0>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="ENG">
<s0>Mouse</s0>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="SPA">
<s0>Ratón</s0>
<s5>11</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE">
<s0>Transduction signal</s0>
<s5>32</s5>
</fC03>
<fC03 i1="12" i2="X" l="ENG">
<s0>Signal transduction</s0>
<s5>32</s5>
</fC03>
<fC03 i1="12" i2="X" l="SPA">
<s0>Transducción señal</s0>
<s5>32</s5>
</fC03>
<fC03 i1="13" i2="X" l="FRE">
<s0>Transferases</s0>
<s2>FE</s2>
<s5>33</s5>
</fC03>
<fC03 i1="13" i2="X" l="ENG">
<s0>Transferases</s0>
<s2>FE</s2>
<s5>33</s5>
</fC03>
<fC03 i1="13" i2="X" l="SPA">
<s0>Transferases</s0>
<s2>FE</s2>
<s5>33</s5>
</fC03>
<fC03 i1="14" i2="X" l="FRE">
<s0>Modélisation</s0>
<s5>34</s5>
</fC03>
<fC03 i1="14" i2="X" l="ENG">
<s0>Modeling</s0>
<s5>34</s5>
</fC03>
<fC03 i1="14" i2="X" l="SPA">
<s0>Modelización</s0>
<s5>34</s5>
</fC03>
<fC03 i1="15" i2="X" l="FRE">
<s0>Animal</s0>
<s5>35</s5>
</fC03>
<fC03 i1="15" i2="X" l="ENG">
<s0>Animal</s0>
<s5>35</s5>
</fC03>
<fC03 i1="15" i2="X" l="SPA">
<s0>Animal</s0>
<s5>35</s5>
</fC03>
<fC03 i1="16" i2="X" l="FRE">
<s0>Imidazo[2,1-b]benzothiazole dérivé</s0>
<s4>INC</s4>
<s5>76</s5>
</fC03>
<fC03 i1="17" i2="X" l="FRE">
<s0>Phénylalaninamide(Nα-[3,5-bis(trifluorométhyl)hénylacétyl]) dérivé</s0>
<s2>NK</s2>
<s4>INC</s4>
<s5>77</s5>
</fC03>
<fC03 i1="18" i2="X" l="FRE">
<s0>Imidazobenzothiazole</s0>
<s4>INC</s4>
<s5>91</s5>
</fC03>
<fC03 i1="19" i2="X" l="FRE">
<s0>Receptor protein-tyrosine kinase</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC03 i1="19" i2="X" l="ENG">
<s0>Receptor protein-tyrosine kinase</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC03 i1="19" i2="X" l="SPA">
<s0>Receptor protein-tyrosine kinase</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE">
<s0>Rodentia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG">
<s0>Rodentia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA">
<s0>Rodentia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE">
<s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG">
<s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA">
<s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE">
<s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG">
<s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA">
<s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE">
<s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="ENG">
<s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="SPA">
<s0>Enzima</s0>
<s2>FE</s2>
</fC07>
<fN21>
<s1>303</s1>
</fN21>
</pA>
</standard>
<server>
<NO>PASCAL 12-0387743 INIST</NO>
<ET>Identification of new aminoacid amides containing the imidazo[2,1-b] benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling</ET>
<AU>FURLAN (Alessandro); COLOMBO (Francesco); KOVER (Andrea); ISSALY (Nathalie); TINTORI (Cristina); ANGELI (Lucilla); LEROUX (Vincent); LETARD (Sebastien); AMAT (Mercedes); ASSES (Yasmine); MAIGRET (Bernard); DUBREUIL (Patrice); BOTTA (Maurizio); DONO (Rosanna); BOSCH (Joan); PICCOLO (Oreste); PASSARELLA (Daniele); MAINA (Flavio)</AU>
<AF>Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907/13288 Marseille/France (1 aut., 4 aut., 14 aut., 18 aut.); Dipartimento di Chimica Organica e Indusriale, Università degli Studi di Milano, Via Venezian 21/20133 Milano/Italie (2 aut., 17 aut.); Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona/08028 Barcelona/Espagne (3 aut., 9 aut., 15 aut.); Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2/53100 Siena/Italie (5 aut., 6 aut., 13 aut.); Nancy Université, LORIA-UMR 7503, Equipe projet Orpailleur, Campus scientifique, BP 239/54506 Vandœuvre-lès-Nancy/France (7 aut., 10 aut., 11 aut.); University of Oslo, Chemistry Department, P.O. Box 1033 Blindern/0315 Oslo/Norvège (7 aut.); Centre de Recherche en Cancérologie de Marseille -U891 INSERM, Institut Paoli-Calmettes, Université de la Méditerranée 27, boulevard Lei Roure BP 30059/13273 Marseille/France (8 aut., 12 aut.); Studio di consulenza scientifica, Via Bornò 5/23896 Sirtori (LC/Italie (16 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>European journal of medicinal chemistry; ISSN 0223-5234; Coden EJMCA5; Royaume-Uni; Da. 2012; Vol. 47; Pp. 239-254; Bibl. 50 ref.</SO>
<LA>Anglais</LA>
<EA>The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting.</EA>
<CC>002B02R01</CC>
<FD>Aminoamide; Gène onc; Inhibiteur; Carcinogenèse; Mode liaison; Anticancéreux; Activité biologique; Modèle moléculaire; Synthèse chimique; Fluor Composé organique; Souris; Transduction signal; Transferases; Modélisation; Animal; Imidazo[2,1-b]benzothiazole dérivé; Phénylalaninamide(Nα-[3,5-bis(tri fluorométhyl)hénylacétyl]) dérivé; Imidazobenzothiazole; Receptor protein-tyrosine kinase</FD>
<FG>Rodentia; Mammalia; Vertebrata; Enzyme</FG>
<ED>Aminoamide; Onc gene; Inhibitor; Carcinogenesis; Binding mode; Antineoplastic agent; Biological activity; Molecular model; Chemical synthesis; Fluorine Organic compounds; Mouse; Signal transduction; Transferases; Modeling; Animal; Receptor protein-tyrosine kinase</ED>
<EG>Rodentia; Mammalia; Vertebrata; Enzyme</EG>
<SD>Aminoamida; Gen onc; Inhibidor; Carcinogénesis; Modo de enlace; Anticanceroso; Actividad biológica; Modelo molecular; Síntesis química; Fluor Compuesto orgánico; Ratón; Transducción señal; Transferases; Modelización; Animal; Receptor protein-tyrosine kinase</SD>
<LO>INIST-12640.354000508861270270</LO>
<ID>12-0387743</ID>
</server>
</inist>
</record>

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