Colección INTI +


Título: Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines
Fuente: Anti-Cancer Agents in Medicinal Chemistry, 14(6)
Autor/es: Cardama, Georgina A.; Comin, Maria J.; Hornos, Leandro; Gonzalez, Nazareno; Defelipe, Lucas; Turjanski, Adrian G.; Alonso, Daniel F.; Gomez, Daniel E.; Lorenzano Menna, Pablo
Materias: Cáncer; Glándulas mamarias; Biología molecular; Células; Inhibidores; Tecnología médica; Lucha contra las enfermedades
Editor/Edición: Bentham Science Publishers; 2014
Licencia: info:eu-repo/semantics/openAccess;
Afiliaciones: Cardama, Georgina A. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular (UNQ); Argentina
Comin, Maria J. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Hornos, Leandro. Instituto Nacional de Tecnología Industrial. INTI-Química; Argentina
Gonzalez, Nazareno. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular (UNQ); Argentina
Defelipe, Lucas. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales (FCEN-UBA); Argentina
Turjanski, Adrian G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales (FCEN-UBA); Argentina
Alonso, Daniel F. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular (UNQ); Argentina
Gomez, Daniel E. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular (UNQ); Argentina
Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Laboratorio de Oncología Molecular (UNQ); Argentina

Resumen: Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of 1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy.
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