Rhosin
目录号 : GC33167
An inhibitor of the Rho-GEF protein-protein interaction
Cas No.:1173671-63-0
Sample solution is provided at 25 µL, 10mM.
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Rhosin is an inhibitor of the protein-protein interaction between Rho and guanine nucleotide exchange factors (GEFs).1 It inhibits RhoA activity when used at concentrations of 10 and 30 ?M and selectively reduces the number and size of MCF-7 breast cancer cell mammospheres over MCF-10A non-cancerous cell mammospheres. It also inhibits migration and invasion of MCF-7 cells and human mammary epithelial cells expressing RhoC. Rhosin (30 ?M) increases neurite outgrowth in PC12 cells. It prevents social defeat stress-induced hyperexcitability and increases spine density in nucleus accumbens dopamine 1 receptor medium spiny neurons (D1-MSNs) when administered post-social defeat stress in a mouse model of depression at a dose of 40 mg/kg.2 It also prevents social defeat stress-induced social avoidance and reductions in sucrose preference in the same model.
1.Shang, X., Marchioni, F., Sipes, N., et al.Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPasesChem. Biol.19(6)699-710(2012) 2.Francis, T.C., Gaynor, A., Chandra, R., et al.The selective RhoA inhibitor rhosin promotes stress resiliency through enhancing D1-medium spiny neuron plasticity and reducing hyperexcitabilityBiol. Psychiatry85(12)1001-1010(2019)
| Cas No. | 1173671-63-0 | SDF | |
| Canonical SMILES | O=C(N/N=C/C1=CC=C2N=CC=NC2=C1)[C@H](N)CC3=CNC4=C3C=CC=C4 | ||
| 分子式 | C20H18N6O | 分子量 | 358.4 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7902 mL | 13.9509 mL | 27.9018 mL |
| 5 mM | 0.558 mL | 2.7902 mL | 5.5804 mL |
| 10 mM | 0.279 mL | 1.3951 mL | 2.7902 mL |
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Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells
Biomedicines 2021 Jan 4;9(1):35.PMID:33406809DOI:10.3390/biomedicines9010035.
The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear whether Rhosin, a Rho inhibitor, acts by suppressing metastasis by a downstream inhibition of Rho. In this study, we investigated this mechanism of metastasis in highly metastatic melanoma and breast cancer cells, and the mechanism of inhibition of metastasis by Rhosin. We found that Rhosin suppressed the RhoA and RhoC activation, the nuclear localization of YAP, but did not affect ERK1/2, Akt, or NF-κB activation in the highly metastatic cell lines B16BL6 and 4T1. High expression of YAP was associated with poor overall and recurrence-free survival in patients with breast cancer or melanoma. Treatment with Rhosin inhibited lung metastasis in vivo. Moreover, Rhosin inhibited tumor cell adhesion to the extracellular matrix via suppression of RHAMM expression, and inhibited SDF-1-induced cell migration and invasion by decreasing CXCR4 expression in B16BL6 and 4T1 cells. These results suggest that the inhibition of RhoA/C-YAP pathway by Rhosin could be an extremely useful therapeutic approach in patients with melanoma and breast cancer.
Small chemical compounds Y16 and Rhosin can inhibit calcium sensitization pathway in vascular smooth muscle cells of spontaneously hypertensive rats
J Formos Med Assoc 2021 Oct;120(10):1863-1868.PMID:33893012DOI:10.1016/j.jfma.2021.03.031.
Background/purpose: The small-molecule compounds Y16 and Rhosin can inhibit the activation of leukemia-associated Rho guanine nucleotide exchange factor (LARG) and small G-protein RhoA, respectively, in breast cancer cells and inhibit their growth and migration. However, it remains unclear whether they have inhibitory effects on the vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs). Methods: Primary cultured VSMCs from SHRs were treated with different concentrations of Y16 or Y16 plus Rhosin for 24 h, followed by 10-min stimulation with 10-7 M angiotensin II (Ang II). The cells were then harvested, and the total protein was extracted. The co-immunoprecipitation method, Western blot analysis, and MTT assay were performed to determine the LARG-RhoA interaction, the protein levels of RhoA and MYPT1, and cell viability, respectively. Results: Y16 dose-dependently inhibited the LARG-RhoA complex formation induced by Ang II. With 50 μM of Y16, the effect of inhibition was statistically significant. Y16 also reduced the formation of phospho-MYPT1 stimulated by Ang II. With 5 μM of Y16, the inhibitory effect was statistically significant. When 25 μM of Y16 and 25 μM of Rhosin were combined, the inhibitory effect on LARG-RhoA interaction was statistically significant. When Y16 and Rhosin were combined, a significantly reduced concentration could effectively inhibit MYPT1 phosphorylation (2.5 μM compared with 5 μM for Y16 alone). Conclusion: Treating SHR VSMCs with Y16 can suppress the activation of LARG, prevent LARG binding to RhoA, and decrease the phosphorylation of MYPT1, thus weakening the activation of the calcium (Ca2+) sensitization pathway in SHR VSMCs.
The Selective RhoA Inhibitor Rhosin Promotes Stress Resiliency Through Enhancing D1-Medium Spiny Neuron Plasticity and Reducing Hyperexcitability
Biol Psychiatry 2019 Jun 15;85(12):1001-1010.PMID:30955841DOI:10.1016/j.biopsych.2019.02.007.
Background: Nucleus accumbens dopamine 1 receptor medium spiny neurons (D1-MSNs) play a critical role in the development of depression-like behavior in mice. Social defeat stress causes dendritic morphological changes on this MSN subtype through expression and activation of early growth response 3 (EGR3) and the Rho guanosine triphosphatase RhoA. However, it is unknown how RhoA inhibition affects electrophysiological properties underlying stress-induced susceptibility. Methods: A novel RhoA-specific inhibitor, Rhosin, was used to inhibit RhoA activity following chronic social defeat stress. Whole-cell electrophysiological recordings of D1-MSNs were performed to assess synaptic and intrinsic consequences of Rhosin treatment on stressed mice. Additionally, recorded cells were filled and analyzed for their morphological properties. Results: We found that RhoA inhibition prevents both D1-MSN hyperexcitability and reduced excitatory input to D1-MSNs caused by social defeat stress. Nucleus accumbens-specific RhoA inhibition is capable of blocking susceptibility caused by D1-MSN EGR3 expression. Lastly, we found that Rhosin enhances spine density, which correlates with D1-MSN excitability, without affecting overall dendritic branching. Conclusions: These findings demonstrate that pharmacological inhibition of RhoA during stress drives an enhancement of total spine number in a subset of nucleus accumbens neurons that prevents stress-related electrophysiological deficits and promotes stress resiliency.
Structure-Activity Relationship Analysis of Rhosin, a RhoA GTPase Inhibitor, Reveals a New Class of Antiplatelet Agents
Int J Mol Sci 2023 Feb 19;24(4):4167.PMID:36835579DOI:10.3390/ijms24044167.
Current antiplatelet therapies have several clinical complications and are mostly irreversible in terms of suppressing platelet activity; hence, there is a need to develop improved therapeutic agents. Previous studies have implicated RhoA in platelet activation. Here, we further characterized the lead RhoA inhibitor, Rhosin/G04, in platelet function and present structure-activity relationship (SAR) analysis. A screening for Rhosin/G04 analogs in our chemical library by similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. A screening for Rhosin/G04 analogs in our chemical library using similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. SAR analysis revealed that the active compounds have a quinoline group optimally attached to the hydrazine at the 4-position and halogen substituents at the 7- or 8-position. Having indole, methylphenyl, or dichloro-phenyl substituents led to better potency. Rhosin/G04 contains a pair of enantiomers, and S-G04 is significantly more potent than R-G04 in inhibiting RhoA activation and platelet aggregation. Furthermore, the inhibitory effect is reversible, and S-G04 is capable of inhibiting diverse-agonist-stimulated platelet activation. This study identified a new generation of small-molecule RhoA inhibitors, including an enantiomer capable of broadly and reversibly modulating platelet activity.
The role of Astragalus polysaccharides in promoting IEC-6 cell migration from polyamine-mediated Ca2+ regulation
Int J Biol Macromol 2022 May 15;207:179-192.PMID:35217086DOI:10.1016/j.ijbiomac.2022.02.109.
Astragalus polysaccharide (APS) has a protective effect on injured intestinal mucosa by promoting intestinal cell migration, but the specific mechanism is unclear. The polyamine-mediated calcium signaling pathway is an important mechanism of cell migration, generally, and we tested the hypothesis that APS can protect damaged intestinal mucosa through the polyamine-mediated calcium signaling pathway. High-performance liquid chromatography (HPLC), infrared chromatography, cell scratch test, Western blot, co-immunoprecipitation, polyamine inhibitor (DFMO), si-Cav1, RhoA inhibitor (Rhosin) and Rac1 inhibitor (NSC23766) were used to detect the pharmacodynamic of APS. The results show that APS can promote cell migration. In addition, APS increased the formations of RhoA/TRPC1, Cav1/TRPC1, and Rac1/PLCγ-1 complexes as well as the expressions of TRPC1, PLCγ-1, RhoA, Cav1, and Rac1, and it reversed the inhibitory effect of DFMO on the above factors. APS also reversed the inhibitory effect of si-Cav1 on Cav1 expression, cytoplasmic Ca2+ concentrations ([Ca2+]cyt), and cell migration. Moreover, APS removed the inhibition of NSC23766 and Rhosin on [Ca2+]cyt and cell migration. In vivo study, the water extract of Astragalus membranaceus (WEA) (15 g/kg) reduced the indomethacin-induced injury of intestinal mucosa as well. These observations suggest that APS can treat gastrointestinal mucosal injury through the polyamine calcium signaling pathway.