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Artículo

Development of an Improved Guanidine-Based Rac1 Inhibitor with in vivo Activity against Non-Small Cell Lung Cancer

Ciarlantini, Matias Sebastián; Barquero, Andrea AlejandraIcon ; Bayo Fina, Juan MiguelIcon ; Wetzler, Diana ElenaIcon ; Dodes Traian, Martín MiguelIcon ; Bucci, Hernán AndrésIcon ; Fiore, Esteban JuanIcon ; Gandolfi Donadío, LucíaIcon ; Defelipe, Lucas AlfredoIcon ; Turjanski, AdrianIcon ; Ramirez, Javier AlbertoIcon ; Mazzolini Rizzo, Guillermo DanielIcon ; Comin, Maria JulietaIcon
Fecha de publicación: 03/2021
Editorial: Wiley VCH Verlag
Revista: Chemmedchem
ISSN: 1860-7179
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Químicas

Resumen

The Rho GTPase Rac1 is involved in the control of cytoskeleton reorganization and other fundamental cellular functions. Aberrant activity of Rac1 and its regulators is common in human cancer. In particular, deregulated expression/activity of Rac GEFs, responsible for Rac1 activation, has been associated to a metastatic phenotype and drug resistance. Thus, the development of novel Rac1-GEF interaction inhibitors is a promising strategy for finding new preclinical candidates. Here, we studied structure–activity relationships within a new family of N,N’-disubstituted guanidine as Rac1 inhibitors. We found that compound 1D-142, presents superior antiproliferative activity in human cancer cell lines and higher potency as Rac1-GEF interaction inhibitor in vitro than parental compounds. In addition, 1D-142 reduces Rac1-mediated TNFα-induced NF-κB nuclear translocation during cell proliferation and migration in NSCLC. Notably, 1D-142 allowed us to show for the first time the application of a Rac1 inhibitor in a lung cancer animal model.
Palabras clave: LUNG CANCER , N,N′-DISUBSTITUTED GUANIDINES , PROTEIN–PROTEIN INTERACTION INHIBITORS , RAC1 INHIBITORS
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/141354
URL: https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202000763
DOI: http://dx.doi.org/10.1002/cmdc.202000763
Colecciones
Articulos(IQUIBICEN)
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Articulos(UMYMFOR)
Articulos de UNID.MICROANAL.Y MET.FISICOS EN QUIM.ORG.(I)
Citación
Ciarlantini, Matias Sebastián; Barquero, Andrea Alejandra; Bayo Fina, Juan Miguel; Wetzler, Diana Elena; Dodes Traian, Martín Miguel; et al.; Development of an Improved Guanidine-Based Rac1 Inhibitor with in vivo Activity against Non-Small Cell Lung Cancer; Wiley VCH Verlag; Chemmedchem; 16; 6; 3-2021; 1011-1021
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