Artículo
Development of a New and Improved Guanidine-based Rac1 Inhibitor with in Vivo Activity against Non-Small Cell Lung Cancer
Ciarlantini, Matias Sebastián; Barquero, Andrea Alejandra
; Wetzler, Diana Elena
; Bayo Fina, Juan Miguel
; Dodes Traian, Martín Miguel
; Bucci, Hernán Andrés
; Fiore, Esteban Juan
; Gandolfi Donadío, Lucía
; Defelipe, Lucas Alfredo
; Turjanski, Adrian
; Ramirez, Javier Alberto
; Mazzolini Rizzo, Guillermo Daniel
; Comin, Maria Julieta
Fecha de publicación:
07/2020
Editorial:
ChemRxiv
Revista:
ChemRxiv
e-ISSN:
2573-2293
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Rac1 (Ras-related C3 botulinum toxin substrate 1), is a member of the family of Rho GTPases involved in the dynamic control of cytoskeleton reorganization and other fundamental cellular functions including growth, motility and survival. Aberrant activity of Rac1 and its regulators is common in human cancer. In particular, deregulated expression/activity of Rac Guanine nucleotide Exchange Factors (GEFs), responsible for Rac activation, has been largely 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. In this work, we have studied structure-activity relationships within a new family of N,N’-disubstituted guanidine as Rac1-GEF protein-protein interaction inhibitors, starting from our first developed member 1A-116. We found that new analogue 1D-142, bearing a pyridine ring instead of benzene ring, presents improved antiproliferative activity in human cancer cell lines and higher potency as Rac1-GEF interaction inhibitor in vitro. In addition, 1D-142 reduces TNFα-induced NF-κB nuclear translocation, a mechanisms mediated by Rac1 during cell proliferation and migration in NSCLC. Notably, 1D-142 was used to show for the first time the application of a Rac1 inhibitor in a lung cancer animal model.
Palabras clave:
RAC
,
GTPASE INHIBITORS
,
TIAM
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Articulos(IIMT)
Articulos de INSTITUTO DE INVESTIGACIONES EN MEDICINA TRASLACIONAL
Articulos de INSTITUTO DE INVESTIGACIONES EN MEDICINA TRASLACIONAL
Articulos(IQUIBICEN)
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
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)
Articulos de UNID.MICROANAL.Y MET.FISICOS EN QUIM.ORG.(I)
Citación
Ciarlantini, Matias Sebastián; Barquero, Andrea Alejandra; Wetzler, Diana Elena; Bayo Fina, Juan Miguel; Dodes Traian, Martín Miguel; et al.; Development of a New and Improved Guanidine-based Rac1 Inhibitor with in Vivo Activity against Non-Small Cell Lung Cancer; ChemRxiv; ChemRxiv; 7-2020; 1-48
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Ciarlantini, Matias Sebastián; Barquero, Andrea Alejandra ; Bayo Fina, Juan Miguel ; Wetzler, Diana Elena ; Dodes Traian, Martín Miguel ; Bucci, Hernán Andrés ; Fiore, Esteban Juan ; Gandolfi Donadío, Lucía ; Defelipe, Lucas Alfredo ; Turjanski, Adrian ; Ramirez, Javier Alberto ; Mazzolini Rizzo, Guillermo Daniel ; Comin, Maria Julieta (Wiley VCH Verlag, 2021-03)