1 research outputs found
Development of a New and Improved Guanidine-based Rac1 Inhibitor with in Vivo Activity against Non-Small Cell Lung Cancer
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.</p