AR-42 (OSU-HDAC42)
目录号 : GC14590HDAC inhibitor,novel and potent
Cas No.:935881-37-1
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment [1]: | |
In vitro HDAC assay |
HDAC activity was analyzed by using an HDAC assay kit. This assay was based on the ability of DU-145 nuclear extract, which is rich in HDAC activity, to mediate the deacetylation of the biotinylated [3H]-acetyl histone H4 peptide that was bound to streptavidin agarose beads. The release of [3H]-acetate into the supernatant was measured to calculate the HDAC activity. Sodium butyrate (0.25 ~ 1 mM) was used as a positive control. |
Cell experiment [1]: | |
Cell lines |
DU-145 cells |
Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months. |
Reaction Conditions |
10 ~ 1000 nM; 96 hrs |
Applications |
AR-42 inhibited the growth of DU-145 cells with an IC50 value of 0.11 μM. |
Animal experiment [2]: | |
Animal models |
Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells |
Dosage form |
25 mg/kg, q.d., or 50 mg/kg, q.o.d.; p.o.; for 28 days |
Applications |
At the doses of 25 mg and 50 mg, AR-42 inhibited the growth of PC-3 tumor xenografts by 52% and 67%, respectively. |
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
References: [1]. Lu Q, Wang DS, Chen CS, Hu YD, Chen CS. Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors. J Med Chem. 2005 Aug 25;48(17):5530-5. [2]. Kulp SK, Chen CS, Wang DS, Chen CY, Chen CS. Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clin Cancer Res. 2006 Sep 1;12(17):5199-206. |
AR-42 (also known as OSU-HDAC42), a derivative of hydroxamate-tethered phenylbutyrate, is a novel and potent inhibitor of histone deacetylase (HDAC) that potently inhibits the activity of HDAC with 50% inhibition concentration IC50 value of 16 nM and induces histone H3 acetylation, α-tubulin acetylation and p21 up-regulation, which have been considered as the hallmark indicators of HDAC inhibition. AR-42 has been found to modulate several apoptosis inhibitors as well as cell survival regulator, including Akt, Bcl-xL, Bax, Ku70 and surviving, and exert potent antitumor activity against multiple tumor types, such as human prostate and hepatic cancers, at least partially through PI3K/Akt pathway inhibition.
Reference
[1].Matthew L. Bush†, Janet Oblinger†, Victoria Brendel, Griffin Santarelli, Jie Huang, Elena M. Akhmametyeva, Sarah S. Burns, Justin Wheeler, Jeremy Davis, Charles W. Yates, Abhik R. Chaudhury, Samuel Kulp, Ching-Shih Chen, Long-Sheng Chang, D. Bradley Welling, and Abraham Jacob. AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. Neuro-Oncology 13(9):983–999, 2011
[2].Aaron M. Sargeant, Robert C. Rengel, Samuel K. Kulp, et al. OSU-HDAC42, a Histone Deacetylase Inhibitor, Blocks Prostate Tumor Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model Cancer Res 2008;68:3999-4009.
[3].Qiang Lu, Da-Sheng Wang, Chang-Shi Chen, Yuan-Dong Hu, and Ching-Shih Chen. Structure-Based Optimization of Phenylbutyrate-Derived Histone Deacetylase
[4].Inhibitors. J. Med. Chem. 2005, 48, 5530-5535
Cas No. | 935881-37-1 | SDF | |
化学名 | N-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide | ||
Canonical SMILES | CC(C)C(C1=CC=CC=C1)C(=O)NC2=CC=C(C=C2)C(=O)NO | ||
分子式 | C18H20N2O3 | 分子量 | 312.36 |
溶解度 | ≥ 15.62 mg/mL 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。 |
||
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。 |
制备储备液 | |||
1 mg | 5 mg | 10 mg | |
1 mM | 3.2014 mL | 16.0072 mL | 32.0143 mL |
5 mM | 0.6403 mL | 3.2014 mL | 6.4029 mL |
10 mM | 0.3201 mL | 1.6007 mL | 3.2014 mL |
第一步:请输入基本实验信息(考虑到实验过程中的损耗,建议多配一只动物的药量) | ||||||||||
给药剂量 | mg/kg | 动物平均体重 | g | 每只动物给药体积 | ul | 动物数量 | 只 | |||
第二步:请输入动物体内配方组成(配方适用于不溶于水的药物;不同批次药物配方比例不同,请联系GLPBIO为您提供正确的澄清溶液配方) | ||||||||||
% DMSO % % Tween 80 % saline | ||||||||||
计算重置 |
计算结果:
工作液浓度: mg/ml;
DMSO母液配制方法: mg 药物溶于 μL DMSO溶液(母液浓度 mg/mL,
体内配方配制方法:取 μL DMSO母液,加入 μL PEG300,混匀澄清后加入μL Tween 80,混匀澄清后加入 μL saline,混匀澄清。
1. 首先保证母液是澄清的;
2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
AR-42: A Pan-HDAC Inhibitor with Antitumor and Antiangiogenic Activities in Esophageal Squamous Cell Carcinoma
Purpose: Esophageal squamous cell carcinoma (ESCC) is a refractory malignancy with high morbidity and mortality. Thus, there is an urgent need to find effective targets and agents for ESCC treatment. The purpose of this study was to assess the anti-ESCC effects of a pan-histone deacetylase (HDAC) inhibitor AR-42 and its mechanisms of action. Methods: Immunohistochemical staining was performed to detect HDAC1 expression in ESCC and adjacent tissue samples. MTT assay, Edu cell proliferation test, flow cytometry, and subcutaneous xenograft were used to assess the anti-ESCC effects of AR-42; furthermore, the antiangiogenic activity of AR-42 was evaluated using endothelial cell migration, invasion, and tube formation assays as well as zebrafish angiogenesis assay. Western blot analysis was performed to explore the underlying mechanism of the anti-ESCC activity of AR-42. Results: HDAC1-positive expression was much higher in ESCC cells than in paracancerous tissues, and the elevated HDAC1 expression was a strong indicator of lymph node metastasis and a more advanced TNM stage of ESCC. Moreover, AR-42 potently suppressed ESCC cell growth through cellular proliferation inhibition and apoptosis induction. Moreover, AR-42 displayed a moderate antiangiogenic activity, and it could significantly inhibit the migration, invasion and tubulogenesis of human umbilical vein endothelial cells as well as intersegmental vessel formation in zebrafish at micromolar concentrations. More importantly, the inhibitory activity of AR-42 on ESCC cells and angiogenesis could also be observed in the TE-1 xenograft model. Further studies showed that AR-42 exerts its anti-ESCC effects mainly by upregulating the expression of p21 and blocking the transduction of multiple signaling cascades related to tumor growth, especially Stat3-mediated signaling. Conclusion: Overall, AR-42 has significant potency for inhibiting ESCC cell growth and shows moderate effect in suppressing angiogenesis, displaying strong anti-ESCC effects in vitro and in vivo. Thus, AR-42 deserves further evaluation as a potential candidate for ESCC therapy.
AR-42 induces apoptosis in human hepatocellular carcinoma cells via HDAC5 inhibition
Histone deacetylases (HDACs) play critical roles in apoptosis and contribute to the proliferation of cancer cells. AR-42 is a novel Class I and II HDAC inhibitor that shows cytotoxicity against various human cancer cell lines. The present study aims to identify the target of AR-42 in hepatocellular carcinoma (HCC) as well as evaluate its therapeutic efficacy. We found that HDAC5 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. CCK8 and colony-formation assays showed that HDAC5 overexpression promotes proliferation in HCC cell lines. Treatment with AR-42 decreased HCC cell growth and increased caspase-dependent apoptosis, and this was rescued by HDAC5 overexpression. We demonstrated that AR-42 can inhibit the deacetylation activity of HDAC5 and its downstream targets in vitro and in vivo. Taken together, these results demonstrate for the first time that AR-42 targets HDAC5 and induces apoptosis in human hepatocellular carcinoma cells. AR-42 therefore shows potential as a new drug candidate for HCC therapy.
Synergistic activity of imatinib and AR-42 against chronic myeloid leukemia cells mainly through HDAC1 inhibition
Aims: The aim of this study was to investigate the combinatorial effects of IM and a novel HDAC inhibitor AR-42 on the proliferation, apoptosis, cell cycle arrest, migration and invasion of CML cells, and to explore the underlying mechanisms.
Main methods: We assessed the ability of the pan-HDAC inhibitor AR-42 and IM, to synergistically kill CML cells by survival, apoptosis, cell cycle, migration and invasion assays in vitro. We also assessed the HDAC1 expression by Western blot and real-time PCR. Synergy was calculated using combinatorial indices as determined by CalcuSyn.
Key findings: We found that Combining AR-42 with IM synergistically inhibited CML cell proliferation, enhanced cell apoptosis, induced cell cycle arrest, and decreased migration and invasion. The expression of HDAC1 in K562R cells was higher than that in K562 cells. AR-42 enhanced IM-induced HDAC1 expression inhibition in K562 and K562R cells. Importantly, HDAC1 overexpression partly reversed the apoptosis, G2/M phase arrest, migration and invasion of K562 cells induced by the combination of IM with AR-42. Moreover, HDAC1 knockdown partly promoted K562R cell apoptosis and G2/M phase arrest, migration and invasion induced by IM in combination with AR-42.
Significance: In conclusion, AR-42 may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating HDAC1 expression. This study provides new insights into the effects of combined therapy using IM and pan-HDAC inhibitor AR-42, paving the way for overcoming IM resistance in clinical practice.
Synergy of Histone-Deacetylase Inhibitor AR-42 with Cisplatin in Bladder Cancer
Purpose: Cisplatin based chemotherapy regimens form the basis of systemic bladder cancer treatment, although they show limited response rates and efficacy. Recent molecular analysis of bladder cancer revealed a high incidence of mutations in chromatin regulatory genes, suggesting a therapeutic avenue for histone deacetylase inhibitors. We investigated the ability of the novel histone deacetylase inhibitor AR-42 to synergize with cisplatin in preclinical models of bladder cancer.
Materials and methods: We assessed the ability of the pan-histone deacetylase inhibitor AR-42 with and without cisplatin to destroy bladder cancer cells by survival and apoptosis assays in vitro, and by growth and differentiation in an in vivo xenograft model. We also assessed the response to the bladder cancer stem cell population by examining the effect of AR-42 on the CD44(+)CD49f(+) population with and without cisplatin. Synergy was calculated using combination indexes.
Results: The AR-42 and cisplatin combination synergistically destroyed bladder cancer cells via apoptosis and it influenced tumor growth and differentiation in vivo. When tested in the CD44(+)CD49f(+) bladder cancer stem cell population, AR-42 showed greater efficacy with and without cisplatin.
Conclusions: AR-42 may be an attractive novel histone deacetylase inhibitor with activity against bladder cancer. Its efficacy in bladder cancer stem cells and synergy with cisplatin warrant further clinical investigation. Our in vitro and animal model studies provide preclinical evidence that AR-42 may be administered in conjunction with cisplatin based chemotherapy to improve the treatment of bladder cancer in patients.
Histone deacetylase inhibitor, AR-42, exerts antitumor effects by inducing apoptosis and cell cycle arrest in Y79 cells
Retinoblastoma (RB) is the most common type of intraocular malignant tumor that occurs in childhood. AR-42, a member of a newly discovered class of phenylbutyrate-derived histone deacetylase inhibitors, exerts antitumor effects on many cancers. In the present study, we initially evaluated the effect of AR-42 towards RB cells and explored the underlying mechanism in this disease. Our results found that AR-42 showed powerful antitumor effects at low micromolar concentrations by inhibiting cell viability, blocking cell cycle, stimulating apoptosis in vitro, and suppressing RB growth in a mouse subcutaneous tumor xenograft model. Furthermore, the AKT/nuclear factor-kappa B signaling pathway was disrupted in Y79 cells treated with AR-42. In conclusion, we propose that AR-42 might be a promising drug treatment for RB.