Structure–activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding

Beausoleil, Eric; Chauvignac, Cédric; Taverne, Thierry; Lacombe, S.; Pognante, Laure; Leblond, Bertrand; Pallares, Diego; Oliveira, Catherine De; Bachelot, F.; Carton, Rachel; Peillon, Hélène; Coutadeur, Séverine; Picard, Virginie; Lambeng, Nathalie; Désiré, Laurent; Schweighoffer, Fabien

doi:10.1016/j.bmcl.2009.08.037

Cited by 18 publications

(17 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In accordance with nucleotide binding assays from a previous report [20] , berberine was ineffective at 1-3 μmol/L in our study. However, at 10 μmol/L berberine inhibited cell growth with similar potency in all three cell lines.…”

Section: Wwwchinapharcom Ying L Et Alsupporting

confidence: 93%

“…Beausoleil et al recently demonstrated that the 19-amino acid insertion in Rac1b produces a large conformational change and generates a larger nucleotide-binding pocket, which is supposed to confer Rac1b selectivity [20] . This specific nucleotide binding inhibition towards Rac1b could block the anti-apoptotic downstream signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Compared to sanguinarine, berberine has been shown to have a decreased ability to inhibit GTPase [20] . In accordance with nucleotide binding assays from a previous report [20] , berberine was ineffective at 1-3 μmol/L in our study.…”

Section: Wwwchinapharcom Ying L Et Almentioning

confidence: 99%

“…Because of the critical roles of Rac1b in tumorigenesis and metastasis, it is clinically urgent to identify potent Rac1b inhibitors. Sanguinarine, a benzophenanthridine alkaloid, has been recently reported to be a selective Rac1b inhibitor in in vitro nucleotide binding inhibition assays [20] .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation

Wei

et al. 2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Small GTPase Rac1 is a member of the Ras superfamily, which plays important roles in regulation of cytoskeleton reorganization, cell growth, proliferation, migration, etc. The aim of this study was to determine how a constitutively active Rac1b regulated cell proliferation and to investigate the effects of the Rac1b inhibitor sanguinarine. Methods: Three HEK293T cell lines stably overexpressing GFP, Rac1-GFP or Rac1b-GFP were constructed by lentiviral infection. The cells were treated with sanguinarine (1 μmol/L) or its analogue berberine (1 μmol/L) for 4 d. Cell proliferation was evaluated by counting cell numbers and with a BrdU incorporation assay. The levels of cleaved PARP-89 (an apoptosis marker) and cyclin-D1 (a proliferative index) were measured using Western blotting. Results: In 10% serum-containing media, overexpressing either Rac1 or Rac1b did not significantly change the cell proliferation. In the serum-starved media, however, the survival rate of Rac1b cells was significantly increased, whereas that of Rac1 cells was moderately increased. The level of cleaved PARP-89 was significantly increased in serum-starved Rac1 cells, but markedly reduced in serumstarved Rac1b cells. The level of cyclin-D1 was significantly increased in both serum-starved Rac1 and Rac1b cells. Treatment with sanguinarine, but not berberine, inhibited the proliferation of Rac1b cells, which was accompanied by significantly increased the level of PARP-89, and decreased both the level of cyclin-D1 and the percentage of BrdU positive cells. Conclusion: Rac1b enhances the cell proliferation under a growth-limiting condition via both anti-apoptotic and pro-proliferative mechanisms. Sanguinarine, as the specific inhibitor of Rac1b, is a potential therapeutic agent for malignant tumors with up-regulated Rac1b.

show abstract

Section: Wwwchinapharcom Ying L Et Alsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Wwwchinapharcom Ying L Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation

Wei

et al. 2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…However, other Rho GTPases, such as Cdc42, are also affected by this compound. Small molecule compounds have also been synthesized to specifically inhibit the Rac1b splice variant (61). Another report identified ITX3 as a GEF inhibitor that targeted Rac and RhoG interaction with Trio; however, this compound is effective at high 50 -100 M concentrations (62).…”

mentioning

confidence: 99%

Characterization of EHop-016, Novel Small Molecule Inhibitor of Rac GTPase

Montalvo-Ortiz¹,

Castillo‐Pichardo

Hernández

et al. 2012

Journal of Biological Chemistry

182

225

View full text Add to dashboard Cite

Background: Rac is a central regulator of cancer cell migration/invasion and metastasis. Results: EHop-016 inhibits Rac activity with an IC 50 of 1 M. EHop-016 blocks Rac interaction with the Rac exchange factor Vav2, lamellipodia extension, and cell migration. Conclusion: EHop-016 is an effective Rac inhibitor. Significance: EHop-016 has potential as a metastasis therapeutic and for investigations of Rac-regulated cellular responses.

show abstract

Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

et al. 2018

View full text Add to dashboard Cite

Cytotoxic necrotizing factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra-intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work we developed a fluorescent cell-based immunoassay to screen for inhibitors of CNF1-induced Rac1 degradation among 1120 mostly approved drugs. Eleven compounds were found to prevent CNF1-induced Rac1 degradation, and five also showed a protective effect against CNF1-induced multinucleation. Finally, lasalocid, monensin, bepridil, and amodiaquine protected cells from both diphtheria toxin and CNF1 challenges. These data highlight the potential for drug repurposing to fight several bacterial infections and Rac1-based diseases.

show abstract

Structure–activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding

Cited by 18 publications

References 30 publications

Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation

Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation

Characterization of EHop-016, Novel Small Molecule Inhibitor of Rac GTPase

Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

Contact Info

Product

Resources

About