Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity.

Autor:	González N; Laboratory of Molecular Oncology, National University of Quilmes, Bernal, Argentina., Cardama GA; Laboratory of Molecular Oncology, National University of Quilmes, Bernal, Argentina.; National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina., Chinestrad P; Molecular Pharmacology Laboratory, National University of Quilmes, Bernal, Argentina., Robles-Valero J; Centro de Investigación del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC-University of Salamanca, Salamanca, Spain., Rodríguez-Fdez S; Centro de Investigación del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC-University of Salamanca, Salamanca, Spain., Lorenzo-Martín LF; Centro de Investigación del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC-University of Salamanca, Salamanca, Spain., Bustelo XR; Centro de Investigación del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC-University of Salamanca, Salamanca, Spain., Lorenzano Menna P; National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.; Molecular Pharmacology Laboratory, National University of Quilmes, Bernal, Argentina., Gomez DE; Laboratory of Molecular Oncology, National University of Quilmes, Bernal, Argentina.; National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2020 Apr 15; Vol. 8, pp. 240. Date of Electronic Publication: 2020 Apr 15 (Print Publication: 2020).
DOI:	10.3389/fcell.2020.00240
Abstrakt:	In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A-116 is also able to inhibit the oncogenic Rac1 P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development. (Copyright © 2020 González, Cardama, Chinestrad, Robles-Valero, Rodríguez-Fdez, Lorenzo-Martín, Bustelo, Lorenzano Menna and Gomez.)
Databáze:	MEDLINE
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