Structure of Dynasore
CAS No.: 304448-55-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Dynasore is a cell-permeable dynamin inhibitor with an IC50 of 15 μM that blocks cell migration.
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Alsharif, Sarah ; Sharma, Pooja ; Bursch, Karina ; Milliken, Rachel ; Lam, Van ; Fallatah, Arwa , et al.
Abstract: A cytoskeletal protein keratin 19 (K19) is highly expressed in breast cancer but its effects on breast cancer cell mechanics are unclear. In MCF7 cells where K19 expression is ablated,we found that K19 is required to maintain rounded epithelial-like shape and tight cell-cell adhesion. A loss of K19 also lowered cell surface E-cadherin levels. Inhibiting internalization restored cell-cell adhesion of KRT19 knockout cells, suggesting that E-cadherin internalization contributed to defective adhesion. Ultimately, while K19 inhibited cell migration and invasion, it was required for cells to form colonies in suspension. Our results suggest that K19 stabilizes E-cadherin complexes at the cell membrane to maintain cell-cell adhesion which inhibits cell invasiveness but provides growth and survival advantages for circulating tumor cells.
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Keywords: Intermediate filaments ; adherens junction ; breast cancer ; cell migration ; cell morphology ; cell-cell adhesion ; keratin ; keratin 19 ; metastasis
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Characterizing the Role of K19 in Maintaining the Structural Integrity of Breast Cancer Cells
Alsharif, Sarah ;
Abstract: Epithelial to mesenchymal transition is associated with an initial stage of tumor metastasis when cells lose cell-cell adhesion and expression of epithelial markers such as keratin intermediate filament proteins. Keratins are critical for the shape and mechanical integrity of epithelial cells. Among different keratins, Keratin 19 (K19) is highly expressed in various types of cancer including breast cancer and is correlated with a worse patient prognosis. Consistently, K19 expression has been reported to be significantly higher in metastatic breast cancer tumor cells compared to primary tumors. Although knocking down K19 in breast cancer cells increased cell migration, recent studies have shown that increased levels of some keratins can also have a positive impact on metastasis, in part by enabling cells to invade the extracellular matrix collectively. The role of K19 on mechanical properties of cancer cells for cell migration and possible impact on metastasis in breast cancer patients is still unknown. Using K19 knockout (KO) cells in our lab, we found that K19 plays a role in maintaining epithelial cell shape and tight cell-cell adhesion of MCF7 breast cancer cells. Moreover, K19 ablation increased the migratory potential but decreased survival potential of MCF7 cells. At the molecular level, Ecadherin was surprisingly found to be overexpressed in KRT19 KO cells. However, we found that E-cadherin binding to β-catenin decreased in K19 KO cells that have less membrane-Ecadherin. Moreover, E-cadherin was found to be accumulated and internalized in early and recycling endocytic compartments in KRT19 KO cells. Inhibiting internalization of cell surface proteins restored cell-cell adhesion of KRT19 KO cells, suggesting that internalization of Ecadherin contributes to defective cell-cell adhesion. Ultimately, while K19 inhibited cell migration, it was required for cells to form colonies in suspension. Our results suggest that K19 stabilizes E-cadherin complexes at the cell membrane to maintain rounded shape and tight cellcell adhesion and this adhesion inhibits cell migration but provides growth and survival advantages for circulating tumor cells. These findings provide context-dependent roles of K19 during metastasis.
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CAS No. : | 304448-55-3 |
Formula : | C18H14N2O4 |
M.W : | 322.31 |
SMILES Code : | O=C(N/N=C/C1=CC=C(O)C(O)=C1)C2=C(O)C=C3C=CC=CC3=C2 |
MDL No. : | MFCD00292551 |
InChI Key : | SYNDQCRDGGCQRZ-VXLYETTFSA-N |
Pubchem ID : | 135533054 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302+H312-H315-H318-H411 |
Precautionary Statements: | P264-P270-P273-P280-P301+P312+P330-P302+P352+P312-P305+P351+P338+P310-P332+P313-P391-P501 |
Class: | 9 |
UN#: | 3077 |
Packing Group: | Ⅲ |
Target |
|
In Vitro:
Cell Line
|
Concentration | Treated Time | Description | References |
mouse alveolar macrophages | 100 μM | 1 h | Inhibited the internalization of influenza A virus, indicating a clathrin-coated pit or caveolin-dependent mechanism of internalization | PMC5507984 |
B103 rat neuroblastoma cells | 80 μM | 30 min | Inhibition of clathrin-mediated endocytosis, reducing the detection of α-syn-positive particles | PMC5466770 |
BG2-c2 cells | 20 μM | 30 min | Dynasore does not affect Gbb-induced receptor internalization, indicating that macropinocytosis is dynamin-independent. | PMC6368546 |
Caco-2 cells | 120 µM | 3 h | Dynasore had a marked inhibitory effect on EV7 infection, indicating that EV7 infection depends on dynamin and clathrin-mediated endocytosis | PMC3324788 |
Bone marrow-derived macrophages (BMDMs) | 5 μM, 10 μM, 25 μM, 50 μM | 1 h | To investigate the effect of dynasore on classical activation of macrophages induced by LPS, results showed that dynasore significantly reduced the mRNA and protein levels of key proinflammatory cytokines including IL-6 and IL-12. | PMC11055558 |
Bone marrow-derived macrophages (BMDMs) | 5 μM, 10 μM, 25 μM, 50 μM | 3 h | To investigate the effect of dynasore on NLRP3 inflammasome activation and pyroptosis, results showed that dynasore effectively inhibited the release of caspase-1 p10 and reduced GSDMD N-terminal and LDH release, indicating that dynasore inhibited NLRP3 inflammasome activation and pyroptosis. | PMC11055558 |
In Vivo:
Species
|
Animal Model
|
Administration | Dosage | Frequency | Description | References |
mice | influenza A virus infection model | intranasal administration | 0.02 mg/kg or 0.2 mg/kg | once daily for 3 days | Suppressed endosomal NOX2 oxidase activity, significantly reducing the pathogenicity of influenza A virus | PMC5507984 |
Mice | LPS-induced acute lung injury model | Intraperitoneal injection | 10 mg/kg, 30 mg/kg, 50 mg/kg | Single dose, lasting 3 hours | To investigate the effect of dynasore on LPS-induced acute lung injury, results showed that dynasore significantly reduced lung injury scores and decreased proinflammatory cytokine levels in both BALF and serum, including IL-1β and IL-6. | PMC11055558 |
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1mg | 5mg | 10mg |
1 mM 5 mM 10 mM |
3.10mL 0.62mL 0.31mL |
15.51mL 3.10mL 1.55mL |
31.03mL 6.21mL 3.10mL |
[1]Macia E, et al. Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell. 2006 Jun;10(6):839-50.
Tags: Dynasore | Dynamin | HSV | Autophagy | Virus Protease | Herpes simplex virus | 304448-55-3
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