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manuscript Ciarlantini et al 09-10-2020.pdf (1.14 MB)

Development of a New and Improved Guanidine-based Rac1 Inhibitor with in Vivo Activity against Non-Small Cell Lung Cancer

preprint
submitted on 13.09.2020 and posted on 16.09.2020 by Matias S Ciarlantini, Andrea Barquero, diana wetzler, Juan Bayo, Martín M. Dodes Traian, Hernan A. Bucci, Esteban J. Fiore, Lucía Gandolfi-Donadío, Lucas Defelipe, Adrián Turjanski, javier a ramirez, Guillermo Mazzolini, Maria Julieta Comin

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.

Funding

(ANPCyT) - Fondo para la Investigación Científica y Tecnológica (FONCyT) PICT-201-0362 to MJC and PICT-2018-1036 to JB, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) PIP2014-2016 to MJC)

History

Email Address of Submitting Author

jcomin@inti.gob.ar

Institution

Instituto Nacionla de Tecnología Industrial, CONICET

Country

Argentina

ORCID For Submitting Author

0000-0003-2187-1932

Declaration of Conflict of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

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