Development of an Improved Guanidine-Based Rac1 Inhibitor with inâ
vivo Activity against Non-Small Cell Lung Cancer.
ChemMedChem
; 16(6): 1011-1021, 2021 03 18.
Article
de En
| MEDLINE
| ID: mdl-33284505
ABSTRACT
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 inâ
vitro than parental compounds. In addition, 1D-142 reduces Rac1-mediated TNFα-induced NF-κB 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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Carcinome pulmonaire non à petites cellules
/
Guanidine
/
Protéine G rac1
/
Développement de médicament
/
Tumeurs du poumon
/
Antinéoplasiques
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
ChemMedChem
Sujet du journal:
FARMACOLOGIA
/
QUIMICA
Année:
2021
Type de document:
Article
Pays d'affiliation:
Argentine