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

Artículo

Autoría

Ciarlantini, Matias Sebastián ; BARQUERO, ANDREA ALEJANDRA ; BAYO FINA, JUAN MIGUEL ; WETZLER, DIANA ELENA ; Dodes Traian, Martín Miguel ; Bucci, Hernán Andrés ; FIORE, ESTEBAN JUAN ; GANDOLFI DONADIO, LUCIA ; Defelipe, Lucas Alfredo ; TURJANSKI, ADRIAN ; RAMIREZ, JAVIER ALBERTO ; MAZZOLINI RIZZO, GUILLERMO DANIEL ; COMIN, MARIA JULIETA

Fecha

2021

Editorial y Lugar de Edición

WILEY-V C H VERLAG GMBH

Revista

CHEMMEDCHEM, vol. 16 (pp. 1011-1021) WILEY-V C H VERLAG GMBH

Resumen Información suministrada por el agente en SIGEVA

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 str... 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 TNF?-induced NF-?B 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.

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Palabras Clave

N,N?-DISUBSTITUTED GUANIDINESLUNG CANCERRAC1 INHIBITORSPROTEIN–PROTEIN INTERACTION INHIBITORS

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http://hdl.handle.net/11336/141354