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

MATIAS S CIARLANTINI; ANDREA BARQUERO; DIANA WETZLER; JUAN BAYO; MARTIN M DODES TRAIAN; HERNAN A. BUCCI; ESTEBAN J FIORE; LUCÍA GANDOLFI-DONADÍO; LUCAS DEFELIPE; ADRIAN TURJANSKI; JAVIER RAMIREZ; GUILLERMO MAZZOLINI; MARÍA JULIETA COMIN

ChemRxiv

ChemRxiv

Año: 2020

2573-2293

The Rho GTPase Rac1 is involved in the control of cytoskeleton reorganization and other fundamental cellular functions. Aber- rant 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 develop- ment 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-kB 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.