| CAS |
No.1357389-11-7 |
| 英文名称 |
RGFP 966 |
| 分子式 |
C21H19FN4O |
| 分子量 |
362.4 |
| 溶解性 |
Soluble in DMSO ≥5mg/mL(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder:-20℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| 运输条件 |
冷藏运输 |
| SMILES |
C1=CC=C(C=C1)C=CCN2C=C(C=N2)C=CC(=O)NC3=C(C=C(C=C3)F)N |
| InChIKey |
BLVQHYHDYFTPDV-VCABWLAWSA-N |
| InChI |
InChI=1S/C21H19FN4O/c22-18-9-10-20(19(23)13-18)25-21(27)11-8-17-14-24-26(15-17)12-4-7-16-5-2-1-3-6-16/h1-11，13-15H，12，23H2，(H，25，27)/b7-4+，11-8+ |
| PubChem CID |
56650312 |
| 靶点 |
HDAC |
| 通路 |
DNA Damage/DNA Repair;Epigenetics;NF-κB |
| 背景说明 |
是一种能够透过血脑屏障的高选择性HDAC3抑制剂。 |
| 生物活性 |
RGFP966 is a highly selective HDAC3 inhibitor with an IC50 of 80 nM and shows no inhibition to other HDACs at concentrations up to 15 μM. RGFP966 can penetrate the blood brain barrier (BBB).[1-4] |
| In Vitro |
RGFP966 在 RAW 264.7 巨噬细胞中有效且选择性地抑制 HDAC 3，IC50 为 0.21 μM，而 HDACs 1 (IC50=5.6 μM)、2 (9.7 μM) 和 8 (>100 μM)，表明对 HDAC 3 具有良好的选择性。HDAC 1、2 和 3 的 mRNA 水平在 RAW 264.7 巨噬细胞中不受 RGFP966 的显著影响，而 HDAC 1 和 HDAC 2 蛋白水平略有影响，尽管在 RGFP966 处理后显著降低。此外，RGFP966 显著降低了 NF-κB p65 的转录活性，而 NF-κB p65 的乙酰化和定位保持不变[2]。 |
| In Vivo |
RGFP966 (10 和 25 mg/kg) 处理显著改善了体重、旋转杆性能和开阔场地运动测试中的多项运动功能指标[3]。RGFP966 以 10 mg/kg 的剂量穿过血脑屏障进入大鼠听觉皮层，具有典型的药代动力学，这共同证明了由于听觉皮层中的作用而调节 A1 可塑性的可行性[4]。 |
| 细胞实验 |
To investigate the influence of the HDAC 3-selective inhibitor RGFP966 on cell viability， RAW 264.7 macrophages， HBE cells and hASM cells are seeded in 96-well plates. To obtain identical cell density at the start of the experiments， RAW 264.7 macrophages are seeded at 25，000 cells/cm2， HBE cells and hASM cells are seeded at 70% confluency (based on surface area) and are serum-starved for 24 h prior incubation with RGFP966. Shortly before incubation with RGFP966， the medium is replaced by 100 μL fresh (if appropriate serum free) culture medium. Incubations with LPS and IFNγ are performed as described for HDAC 1-3 downregulation by siRNA. After 20 h of incubation with RGFP966， 20 μL of CellTiter 96 AQueous One Solution reagent is added to each well and incubated at 37°C for 1 h in the dark. The absorbance at 490 nm is measured using a Synergy H1 plate reader. LPS/IFNγ-stimulated cells without addition of RGFP966 are considered 100%[2]. |
| 动物实验 |
Mice[3] N171-82Q transgenic mice are housed and maintained on a normal 12-h light/dark cycle with lights on at 6:00 a.m and free access to food and water. Mice are administered RGFP966 (10 or 25 mg/kg) for 10 weeks by S.C. injection (3 injections/week) beginning at 8 weeks of age. RGFP966 is dissolved with 75% polyethylene glycol 200/25% sodium acetate (6.25 mM); control mice received an equal volume of drug vehicle. Body weights are recorded twice per week. Mice are sacrificed at 18 weeks of age， 6 h after the final injection by overdose with isofluorane anesthesia. Brains are removed， and striata and cortex dissected out for gene expression assays or intracardially perfused with 4% paraformaldehyde. Rats[4] A total of thirty-three adult male Sprague Dawley rats (275-350 g) are used. Immediately following the daily training session， a posttraining systemic injection of either RGPF966 (10 mg/kg， s.c.) or vehicle (at a comparable volume to drug treatment) is delivered to each subject. |
| 激酶实验 |
The respective human recombinant HDAC enzymes are incubated in absence and/or in presence of various concentrations RGFP966 and a pro-fluorogenic substrate at room temperature for 60 min. Next， the deacetylation reaction is stopped by the addition of the HDAC Stop Solution (6 mg/mL trypsin， 0.3 mM SAHA) in all wells and the plate is incubated at 37°C for 20 min. The release of the fluorescent 7-amino-4-methylcoumarin is monitored by measuring the fluorescence at λem=460 nm and λex=390 nm using a Synergy H1 plate reader. The fluorescence value of the background wells is subtracted from the fluorescence of the positive control， blank and inhibitor wells. Nonlinear regression is used to fit the data to the log(inhibitor) vs. response curve using GraphPad Prism[2]. |
| 数据来源文献 |
[1]. Malvaez M， et al. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2647-52.
[2]. Leus NG， et al. HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity. Biochem Pharmacol. 2016 May 15;108:58-74.
[3]. Jia H， et al. The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington‘s Disease Mice. PLoS One. 2016 Mar 31;11(3):e0152498.
[4]. Bieszczad KM， et al. Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation. J Neurosci. 2015 Sep 23;35(38):13124-32. |
| 规格 |
1mg 5mg 10mg 25mg 50mg |
| 单位 |
瓶 |
中文
英语
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