Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

Autores
González, Nazareno; Cardama, Georgina Alexandra; Chinestrad, Patricio Manuel; Robles Valero, Javier; Rodríguez Fdez, Sonia; Lorenzo Martín, L. Francisco; Bustelo, Xosé R.; Lorenzano Menna, Pablo; Gomez, Daniel Eduardo
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A116 is also able to inhibit the oncogenic Rac1P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.
Fil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Chinestrad, Patricio Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina
Fil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Rodríguez Fdez, Sonia. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Lorenzo Martín, L. Francisco. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
CANCER
DOCKING
GTPASES
INHIBITOR
SMALL-MOLECULE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/142278
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/142278
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network_name_str CONICET Digital (CONICET)
spelling Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological ActivityGonzález, NazarenoCardama, Georgina AlexandraChinestrad, Patricio ManuelRobles Valero, JavierRodríguez Fdez, SoniaLorenzo Martín, L. FranciscoBustelo, Xosé R.Lorenzano Menna, PabloGomez, Daniel EduardoCANCERDOCKINGGTPASESINHIBITORSMALL-MOLECULEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A116 is also able to inhibit the oncogenic Rac1P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.Fil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chinestrad, Patricio Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; ArgentinaFil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Rodríguez Fdez, Sonia. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Lorenzo Martín, L. Francisco. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFrontiers Media2020-04-15info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/142278González, Nazareno; Cardama, Georgina Alexandra; Chinestrad, Patricio Manuel; Robles Valero, Javier; Rodríguez Fdez, Sonia; et al.; Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity; Frontiers Media; Frontiers in Cell and Developmental Biology; 8; 15-4-2020; 1-142296-634XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcell.2020.00240/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fcell.2020.00240info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:43:13Zoai:ri.conicet.gov.ar:11336/142278instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:43:13.73CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
title Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
spellingShingle Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
González, Nazareno
CANCER
DOCKING
GTPASES
INHIBITOR
SMALL-MOLECULE
title_short Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
title_full Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
title_fullStr Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
title_full_unstemmed Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
title_sort Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity
dc.creator.none.fl_str_mv González, Nazareno
Cardama, Georgina Alexandra
Chinestrad, Patricio Manuel
Robles Valero, Javier
Rodríguez Fdez, Sonia
Lorenzo Martín, L. Francisco
Bustelo, Xosé R.
Lorenzano Menna, Pablo
Gomez, Daniel Eduardo
author González, Nazareno
author_facet González, Nazareno
Cardama, Georgina Alexandra
Chinestrad, Patricio Manuel
Robles Valero, Javier
Rodríguez Fdez, Sonia
Lorenzo Martín, L. Francisco
Bustelo, Xosé R.
Lorenzano Menna, Pablo
Gomez, Daniel Eduardo
author_role author
author2 Cardama, Georgina Alexandra
Chinestrad, Patricio Manuel
Robles Valero, Javier
Rodríguez Fdez, Sonia
Lorenzo Martín, L. Francisco
Bustelo, Xosé R.
Lorenzano Menna, Pablo
Gomez, Daniel Eduardo
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CANCER
DOCKING
GTPASES
INHIBITOR
SMALL-MOLECULE
topic CANCER
DOCKING
GTPASES
INHIBITOR
SMALL-MOLECULE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A116 is also able to inhibit the oncogenic Rac1P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.
Fil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Chinestrad, Patricio Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina
Fil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Rodríguez Fdez, Sonia. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Lorenzo Martín, L. Francisco. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A116 is also able to inhibit the oncogenic Rac1P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.
publishDate 2020
dc.date.none.fl_str_mv 2020-04-15
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/142278
González, Nazareno; Cardama, Georgina Alexandra; Chinestrad, Patricio Manuel; Robles Valero, Javier; Rodríguez Fdez, Sonia; et al.; Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity; Frontiers Media; Frontiers in Cell and Developmental Biology; 8; 15-4-2020; 1-14
2296-634X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/142278
identifier_str_mv González, Nazareno; Cardama, Georgina Alexandra; Chinestrad, Patricio Manuel; Robles Valero, Javier; Rodríguez Fdez, Sonia; et al.; Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity; Frontiers Media; Frontiers in Cell and Developmental Biology; 8; 15-4-2020; 1-14
2296-634X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcell.2020.00240/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fcell.2020.00240
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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