Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines
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 me...
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2014
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18715206_v14_n6_p840_Cardama http://hdl.handle.net/20.500.12110/paper_18715206_v14_n6_p840_Cardama |
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paper:paper_18715206_v14_n6_p840_Cardama2023-06-08T16:29:58Z Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines 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 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. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18715206_v14_n6_p840_Cardama http://hdl.handle.net/20.500.12110/paper_18715206_v14_n6_p840_Cardama |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines |
| topic_facet |
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 |
| description |
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. |
| title |
Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines |
| title_short |
Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines |
| title_full |
Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines |
| title_fullStr |
Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines |
| title_full_unstemmed |
Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines |
| title_sort |
preclinical development of novel rac1-gef signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines |
| publishDate |
2014 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18715206_v14_n6_p840_Cardama http://hdl.handle.net/20.500.12110/paper_18715206_v14_n6_p840_Cardama |
| _version_ |
1768544615121551360 |