Artículo

Cardama, G.A.; Comin, M.J.; Hornos, L.; Gonzalez, N.; Defelipe, L.; Turjanski, A.G.; Alonso, D.F.; Gomez, D.E.; Menna, P.L. "Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines" (2014) Anti-Cancer Agents in Medicinal Chemistry. 14(6):840-851
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Abstract:

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. © 2014 Bentham Science Publishers.

Registro:

Documento: Artículo
Título:Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines
Autor:Cardama, G.A.; Comin, M.J.; Hornos, L.; Gonzalez, N.; Defelipe, L.; Turjanski, A.G.; Alonso, D.F.; Gomez, D.E.; Menna, P.L.
Filiación:Laboratorio de Oncología Molecular, Universidad Nacional de Quilmes, Bernal, B1876BXD, Buenos Aires, Argentina
Centro de Investigación y Desarrollo en Química, Instituto Nacional de Tecnología Industrial (INTI) and CONICET, San Martín, B1650WAB, Argentina
Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires C1428EHA, Argentina
Departamento de Química Biológica, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires C1428EHA, Argentina
Palabras clave:Breast cancer; Docking; Rac1 inhibitor; Rational design; Virtual screening; 1a 116; 4 amino 6 [2 [[4 (diethylamino) 1 methylbutyl] amino] 6 methyl 4 pyrimidinyl] 2 methylquinoline; 4 amino 6 [2 [[4 (diethylamino) 1 methylbutyl]amino] 6 methyl 4 pyrimidinyl] 2 methylquinoline; actin; antineoplastic agent; epidermal growth factor; guanine nucleotide exchange factor; peptides and proteins; Rac1 protein; tiam1 protein; unclassified drug; zinc69391; antineoplastic agent; guanidine derivative; guanine nucleotide exchange factor; pyrimidine derivative; Rac1 protein; RAC1 protein, human; ZINC69391; animal cell; animal experiment; animal model; animal tissue; antiproliferative activity; article; bioassay; breast cancer; cell cycle assay; cell cycle progression; cell migration; cell migration assay; cell proliferation; cell proliferation assay; controlled study; drug design; drug identification; female; flow cytometry; human; human cell; IC 50; lung metastasis; metastasis inhibition; molecular docking; mouse; MTT assay; nonhuman; precipitation; protein interaction; pull down assay; screening; signal transduction; animal; antagonists and inhibitors; Breast Neoplasms; cell cycle; chemical structure; chemistry; dose response; drug effects; drug screening; HEK293 cell line; MCF 7 cell line; metabolism; pathology; structure activity relation; synthesis; tumor cell line; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Female; Guanidines; Guanine Nucleotide Exchange Factors; HEK293 Cells; Humans; MCF-7 Cells; Mice; Models, Molecular; Molecular Structure; Pyrimidines; rac1 GTP-Binding Protein; Signal Transduction; Structure-Activity Relationship
Año:2014
Volumen:14
Número:6
Página de inicio:840
Página de fin:851
DOI: http://dx.doi.org/10.2174/18715206113136660334
Título revista:Anti-Cancer Agents in Medicinal Chemistry
Título revista abreviado:Anti-Cancer Agents Med. Chem.
ISSN:18715206
CAS:4 amino 6 [2 [[4 (diethylamino) 1 methylbutyl]amino] 6 methyl 4 pyrimidinyl] 2 methylquinoline, 733767-34-5; epidermal growth factor, 62229-50-9; Antineoplastic Agents; Guanidines; Guanine Nucleotide Exchange Factors; Pyrimidines; rac1 GTP-Binding Protein; RAC1 protein, human; ZINC69391
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18715206_v14_n6_p840_Cardama

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Citas:

---------- APA ----------
Cardama, G.A., Comin, M.J., Hornos, L., Gonzalez, N., Defelipe, L., Turjanski, A.G., Alonso, D.F.,..., Menna, P.L. (2014) . Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anti-Cancer Agents in Medicinal Chemistry, 14(6), 840-851.
http://dx.doi.org/10.2174/18715206113136660334
---------- CHICAGO ----------
Cardama, G.A., Comin, M.J., Hornos, L., Gonzalez, N., Defelipe, L., Turjanski, A.G., et al. "Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines" . Anti-Cancer Agents in Medicinal Chemistry 14, no. 6 (2014) : 840-851.
http://dx.doi.org/10.2174/18715206113136660334
---------- MLA ----------
Cardama, G.A., Comin, M.J., Hornos, L., Gonzalez, N., Defelipe, L., Turjanski, A.G., et al. "Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines" . Anti-Cancer Agents in Medicinal Chemistry, vol. 14, no. 6, 2014, pp. 840-851.
http://dx.doi.org/10.2174/18715206113136660334
---------- VANCOUVER ----------
Cardama, G.A., Comin, M.J., Hornos, L., Gonzalez, N., Defelipe, L., Turjanski, A.G., et al. Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anti-Cancer Agents Med. Chem. 2014;14(6):840-851.
http://dx.doi.org/10.2174/18715206113136660334