InforLorV4, Main, Exploration, bibRecord, 001E93

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 : 001E93 ( Main/Exploration ); précédent : 001E92; suivant : 001E94

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 [France] ; Francesco Colombo [Italie] ; Andrea Kover [Espagne] ; Nathalie Issaly [France] ; Cristina Tintori [Italie] ; Lucilla Angeli [Italie] ; Vincent Leroux [France, Norvège] ; Sebastien Letard [France] ; Mercedes Amat [Espagne] ; Yasmine Asses [France] ; Bernard Maigret [France] ; Patrice Dubreuil [France] ; Maurizio Botta [Italie] ; Rosanna Dono [France] ; Joan Bosch [Espagne] ; Oreste Piccolo [Italie] ; Daniele Passarella [Italie] ; Flavio Maina [France]

Source :

European journal of medicinal chemistry [ 0223-5234 ] ; 2012.

RBID : Pascal:12-0387743

Descripteurs français

Pascal (Inist)
- 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(trifluorométhyl)hénylacétyl]) dérivé, Imidazobenzothiazole, Receptor protein-tyrosine kinase.

English descriptors

KwdEn :
- Aminoamide, Animal, Antineoplastic agent, Binding mode, Biological activity, Carcinogenesis, Chemical synthesis, Fluorine Organic compounds, Inhibitor, Modeling, Molecular model, Mouse, Onc gene, Receptor protein-tyrosine kinase, Signal transduction, Transferases.
mix :
- Amides, Amino Acids, Animals, Antineoplastic Agents, Cell Line, Cell Proliferation, Cell Survival, Dogs, Drug Design, Enzyme Activation, Humans, Imidazoles, Models, Molecular, Protein Conformation, Proto-Oncogene Proteins c-met, Signal Transduction, Tumor, User-Computer Interface.

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.

Url:

https://hal.inria.fr/hal-00763849

Affiliations:

Le document en format XML

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<region nuts="2">Østlandet</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Letard, Sebastien" sort="Letard, Sebastien" uniqKey="Letard S" first="Sebastien" last="Letard">Sebastien Letard</name>
<affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Centre de Recherche en Cancérologie de Marseille -U891 INSERM, Institut Paoli-Calmettes, Université de la Méditerranée 27, boulevard Lei Roure BP 30059</s1>
<s2>13273 Marseille</s2>
<s3>FRA</s3>
<sZ>8 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
<settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Amat, Mercedes" sort="Amat, Mercedes" uniqKey="Amat M" first="Mercedes" last="Amat">Mercedes Amat</name>
<affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona</s1>
<s2>08028 Barcelona</s2>
<s3>ESP</s3>
<sZ>3 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>15 aut.</sZ>
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<country>Espagne</country>
<placeName><region nuts="2" type="communauté">Catalogne</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Asses, Yasmine" sort="Asses, Yasmine" uniqKey="Asses Y" first="Yasmine" last="Asses">Yasmine Asses</name>
<affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Nancy Université, LORIA-UMR 7503, Equipe projet Orpailleur, Campus scientifique, BP 239</s1>
<s2>54506 Vandœuvre-lès-Nancy</s2>
<s3>FRA</s3>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region" nuts="2">Grand Est</region>
<region type="old region" nuts="2">Lorraine (région)</region>
<settlement type="city">Vandœuvre-lès-Nancy</settlement>
</placeName>
<orgName type="university">Nancy-Université</orgName>
</affiliation>
</author>
<author><name sortKey="Maigret, Bernard" sort="Maigret, Bernard" uniqKey="Maigret B" first="Bernard" last="Maigret">Bernard Maigret</name>
<affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Nancy Université, LORIA-UMR 7503, Equipe projet Orpailleur, Campus scientifique, BP 239</s1>
<s2>54506 Vandœuvre-lès-Nancy</s2>
<s3>FRA</s3>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region" nuts="2">Grand Est</region>
<region type="old region" nuts="2">Lorraine (région)</region>
<settlement type="city">Vandœuvre-lès-Nancy</settlement>
</placeName>
<orgName type="university">Nancy-Université</orgName>
</affiliation>
</author>
<author><name sortKey="Dubreuil, Patrice" sort="Dubreuil, Patrice" uniqKey="Dubreuil P" first="Patrice" last="Dubreuil">Patrice Dubreuil</name>
<affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Centre de Recherche en Cancérologie de Marseille -U891 INSERM, Institut Paoli-Calmettes, Université de la Méditerranée 27, boulevard Lei Roure BP 30059</s1>
<s2>13273 Marseille</s2>
<s3>FRA</s3>
<sZ>8 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
<settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Botta, Maurizio" sort="Botta, Maurizio" uniqKey="Botta M" first="Maurizio" last="Botta">Maurizio Botta</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2</s1>
<s2>53100 Siena</s2>
<s3>ITA</s3>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
<country>Italie</country>
<wicri:noRegion>53100 Siena</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Dono, Rosanna" sort="Dono, Rosanna" uniqKey="Dono R" first="Rosanna" last="Dono">Rosanna Dono</name>
<affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907</s1>
<s2>13288 Marseille</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
<settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bosch, Joan" sort="Bosch, Joan" uniqKey="Bosch J" first="Joan" last="Bosch">Joan Bosch</name>
<affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona</s1>
<s2>08028 Barcelona</s2>
<s3>ESP</s3>
<sZ>3 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
<country>Espagne</country>
<placeName><region nuts="2" type="communauté">Catalogne</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Piccolo, Oreste" sort="Piccolo, Oreste" uniqKey="Piccolo O" first="Oreste" last="Piccolo">Oreste Piccolo</name>
<affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Studio di consulenza scientifica, Via Bornò 5</s1>
<s2>23896 Sirtori (LC</s2>
<s3>ITA</s3>
<sZ>16 aut.</sZ>
</inist:fA14>
<country>Italie</country>
<wicri:noRegion>23896 Sirtori (LC</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Passarella, Daniele" sort="Passarella, Daniele" uniqKey="Passarella D" first="Daniele" last="Passarella">Daniele Passarella</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Dipartimento di Chimica Organica e Indusriale, Università degli Studi di Milano, Via Venezian 21</s1>
<s2>20133 Milano</s2>
<s3>ITA</s3>
<sZ>2 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Italie</country>
<wicri:noRegion>20133 Milano</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Maina, Flavio" sort="Maina, Flavio" uniqKey="Maina F" first="Flavio" last="Maina">Flavio Maina</name>
<affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907</s1>
<s2>13288 Marseille</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
<settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">European journal of medicinal chemistry</title>
<title level="j" type="abbreviated">Eur. j. med. chem.</title>
<idno type="ISSN">0223-5234</idno>
<imprint><date when="2012">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">European journal of medicinal chemistry</title>
<title level="j" type="abbreviated">Eur. j. med. chem.</title>
<idno type="ISSN">0223-5234</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aminoamide</term>
<term>Animal</term>
<term>Antineoplastic agent</term>
<term>Binding mode</term>
<term>Biological activity</term>
<term>Carcinogenesis</term>
<term>Chemical synthesis</term>
<term>Fluorine Organic compounds</term>
<term>Inhibitor</term>
<term>Modeling</term>
<term>Molecular model</term>
<term>Mouse</term>
<term>Onc gene</term>
<term>Receptor protein-tyrosine kinase</term>
<term>Signal transduction</term>
<term>Transferases</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Aminoamide</term>
<term>Gène onc</term>
<term>Inhibiteur</term>
<term>Carcinogenèse</term>
<term>Mode liaison</term>
<term>Anticancéreux</term>
<term>Activité biologique</term>
<term>Modèle moléculaire</term>
<term>Synthèse chimique</term>
<term>Fluor Composé organique</term>
<term>Souris</term>
<term>Transduction signal</term>
<term>Transferases</term>
<term>Modélisation</term>
<term>Animal</term>
<term>Imidazo[2,1-b]benzothiazole dérivé</term>
<term>Phénylalaninamide(Nα-[3,5-bis(trifluorométhyl)hénylacétyl]) dérivé</term>
<term>Imidazobenzothiazole</term>
<term>Receptor protein-tyrosine kinase</term>
</keywords>
<keywords scheme="mix" xml:lang="en"><term>Amides</term>
<term>Amino Acids</term>
<term>Animals</term>
<term>Antineoplastic Agents</term>
<term>Cell Line</term>
<term>Cell Proliferation</term>
<term>Cell Survival</term>
<term>Dogs</term>
<term>Drug Design</term>
<term>Enzyme Activation</term>
<term>Humans</term>
<term>Imidazoles</term>
<term>Models</term>
<term>Molecular</term>
<term>Protein Conformation</term>
<term>Proto-Oncogene Proteins c-met</term>
<term>Signal Transduction</term>
<term>Tumor</term>
<term>User-Computer Interface</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><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>
</front>
</TEI>
<affiliations><list><country><li>Espagne</li>
<li>France</li>
<li>Italie</li>
<li>Norvège</li>
</country>
<region><li>Catalogne</li>
<li>Grand Est</li>
<li>Lorraine (région)</li>
<li>Provence-Alpes-Côte d'Azur</li>
<li>Østlandet</li>
</region>
<settlement><li>Marseille</li>
<li>Oslo</li>
<li>Vandœuvre-lès-Nancy</li>
</settlement>
<orgName><li>Nancy-Université</li>
</orgName>
</list>
<tree><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Furlan, Alessandro" sort="Furlan, Alessandro" uniqKey="Furlan A" first="Alessandro" last="Furlan">Alessandro Furlan</name>
</region>
<name sortKey="Asses, Yasmine" sort="Asses, Yasmine" uniqKey="Asses Y" first="Yasmine" last="Asses">Yasmine Asses</name>
<name sortKey="Dono, Rosanna" sort="Dono, Rosanna" uniqKey="Dono R" first="Rosanna" last="Dono">Rosanna Dono</name>
<name sortKey="Dubreuil, Patrice" sort="Dubreuil, Patrice" uniqKey="Dubreuil P" first="Patrice" last="Dubreuil">Patrice Dubreuil</name>
<name sortKey="Issaly, Nathalie" sort="Issaly, Nathalie" uniqKey="Issaly N" first="Nathalie" last="Issaly">Nathalie Issaly</name>
<name sortKey="Leroux, Vincent" sort="Leroux, Vincent" uniqKey="Leroux V" first="Vincent" last="Leroux">Vincent Leroux</name>
<name sortKey="Letard, Sebastien" sort="Letard, Sebastien" uniqKey="Letard S" first="Sebastien" last="Letard">Sebastien Letard</name>
<name sortKey="Maigret, Bernard" sort="Maigret, Bernard" uniqKey="Maigret B" first="Bernard" last="Maigret">Bernard Maigret</name>
<name sortKey="Maina, Flavio" sort="Maina, Flavio" uniqKey="Maina F" first="Flavio" last="Maina">Flavio Maina</name>
</country>
<country name="Italie"><noRegion><name sortKey="Colombo, Francesco" sort="Colombo, Francesco" uniqKey="Colombo F" first="Francesco" last="Colombo">Francesco Colombo</name>
</noRegion>
<name sortKey="Angeli, Lucilla" sort="Angeli, Lucilla" uniqKey="Angeli L" first="Lucilla" last="Angeli">Lucilla Angeli</name>
<name sortKey="Botta, Maurizio" sort="Botta, Maurizio" uniqKey="Botta M" first="Maurizio" last="Botta">Maurizio Botta</name>
<name sortKey="Passarella, Daniele" sort="Passarella, Daniele" uniqKey="Passarella D" first="Daniele" last="Passarella">Daniele Passarella</name>
<name sortKey="Piccolo, Oreste" sort="Piccolo, Oreste" uniqKey="Piccolo O" first="Oreste" last="Piccolo">Oreste Piccolo</name>
<name sortKey="Tintori, Cristina" sort="Tintori, Cristina" uniqKey="Tintori C" first="Cristina" last="Tintori">Cristina Tintori</name>
</country>
<country name="Espagne"><region name="Catalogne"><name sortKey="Kover, Andrea" sort="Kover, Andrea" uniqKey="Kover A" first="Andrea" last="Kover">Andrea Kover</name>
</region>
<name sortKey="Amat, Mercedes" sort="Amat, Mercedes" uniqKey="Amat M" first="Mercedes" last="Amat">Mercedes Amat</name>
<name sortKey="Bosch, Joan" sort="Bosch, Joan" uniqKey="Bosch J" first="Joan" last="Bosch">Joan Bosch</name>
</country>
<country name="Norvège"><region name="Østlandet"><name sortKey="Leroux, Vincent" sort="Leroux, Vincent" uniqKey="Leroux V" first="Vincent" last="Leroux">Vincent Leroux</name>
</region>
</country>
</tree>
</affiliations>
</record>

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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

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

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