T-00127_HEV1
目录号 : GC32199
T-00127_HEV1是一个phosphatidylinositol4-kinaseIIIbeta(PI4KB)抑制剂，其IC50值为60nM。
Cas No.:900874-91-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Kinase experiment: |
The inhibitory effect of T-00127_HEV1 at a concentration of 10 μM on in vitro cellular protein kinase activities is assessed by kinase profiling with an ATP concentration near the Km for each kinase. Inhibitory effects of GW5074, AN-12-H5, and T-00127_HEV1 at a concentration of 10 μM on in vitro PI kinase activities are assessed by the SelectScreen kinase profiling service with an ATP concentration of 10 μM. For T-00127_HEV1, the 50% inhibitory concentration (IC50) for in vitro PI4KB activity is also measured with an ATP concentration of 10 μM[1]. |
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Cell experiment: |
RD cells (1.0×104 cells per well in 100 μL medium) in a 96-well plate are infected with PV1, EV71, or CVB3 at multiplicities of infection (MOI) of 10, 1.0, and 0.1 at 37°C for 1 h in the absence of T-00127_HEV1. The cells are washed three times with 10% FCS-DMEM, followed by the addition of 100 μL of 10% FCS-DMEM containing 10 or 0 μM T-00127_HEV1. Cells are collected at 16 h p.i., and then viral RNA is extracted from the cells using a viral RNA purification kit. The number of copies of the viral genome is quantified using a real-time PCR system[1]. |
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References: [1]. Arita M, et al. Phosphatidylinositol 4-kinase III beta is a target of enviroxime-like compounds for antipoliovirus activity. J Virol. 2011 Mar;85(5):2364-72. |
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T-00127_HEV1 is a phosphatidylinositol 4-kinase III beta (PI4KB) inhibitor with an IC50 of 60 nM.
T-00127_HEV1 shows more potent anti-poliovirus (PV) activity (EC50 of 0.77 μM) than other candidate compounds (EC50 of 1.7 to 4.7 μM). GW5074 and T-00127_HEV1 almost completely inhibit PI4KB kinase activity at 10 μM (3% and 5% of residual activity, respectively), in contrast to AN-12-H5 (108% of activity [no inhibition])[1].
[1]. Arita M, et al. Phosphatidylinositol 4-kinase III beta is a target of enviroxime-like compounds for antipoliovirus activity. J Virol. 2011 Mar;85(5):2364-72.
| Cas No. | 900874-91-1 | SDF | |
| Canonical SMILES | CC1=NC2=C(C3=CC=C(OC)C(OC)=C3)C(C)=NN2C(NCCN4CCOCC4)=C1 | ||
| 分子式 | C22H29N5O3 | 分子量 | 411.5 |
| 溶解度 | DMSO : 50 mg/mL (121.51 mM; Need ultrasonic) | 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。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4301 mL | 12.1507 mL | 24.3013 mL |
| 5 mM | 0.486 mL | 2.4301 mL | 4.8603 mL |
| 10 mM | 0.243 mL | 1.2151 mL | 2.4301 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。
Phosphatidylinositol 4-kinase III beta is a target of enviroxime-like compounds for antipoliovirus activity
J Virol 2011 Mar;85(5):2364-72.PMID:21177810DOI:10.1128/JVI.02249-10.
Enviroxime is an antienterovirus compound that targets viral protein 3A and/or 3AB and suppresses a step in enterovirus replication by unknown mechanism. To date, four antienterovirus compounds, i.e., GW5074, Flt3 inhibitor II, TTP-8307, and AN-12-H5, are known to have similar mutations in the 3A protein-encoding region causing resistance to enviroxime (a G5318A [3A-Ala70Thr] mutation in poliovirus [PV]) and are considered enviroxime-like compounds. Recently, antienterovirus activity of a phosphatidylinositol 4-kinase III beta (PI4KB) inhibitor, PIK93, was reported, suggesting that PI4KB is an important host factor targetable by antienterovirus compounds (N. Y. Hsu et al., Cell 141:799-811, 2010). In this study, we analyzed the inhibitory effects of previously identified enviroxime-like compounds (GW5074 and AN-12-H5) and a newly identified antienterovirus compound, T-00127-HEV1, on phosphoinositide (PI) kinases. We found that T-00127-HEV1 inhibited PI4KB activity with a higher specificity for than other PI kinases, in contrast to GW5074, which had a broad specificity for PI kinases. In contrast, AN-12-H5 showed no inhibitory effect on PI4KB activity and only moderate inhibitory effects on PI 3-kinase activity. Small interfering RNA (siRNA) screening targeting PI kinases identified PI4KB is a target of GW5074 and T-00127-HEV1, but not of AN-12-H5, for anti-PV activity. Interestingly, T-00127-HEV1 and GW5074 did not inhibit hepatitis C virus (HCV) replication, in contrast to a strong inhibitory effect of AN-12-H5. These results suggested that PI4KB is an enterovirus-specific host factor required for the replication process and targeted by some enviroxime-like compounds (T-00127-HEV1 and GW5074) and that enviroxime-like compounds may have targets other than PI kinases for their antiviral effect.
Purine analogs as phosphatidylinositol 4-kinase IIIβ inhibitors
Bioorg Med Chem Lett 2016 Jun 1;26(11):2706-12.PMID:27090557DOI:10.1016/j.bmcl.2016.04.002.
We report on an extensive structure-activity relationship study of novel PI4K IIIβ inhibitors. The purine derivative of the potent screening hit T-00127-HEV1 has served as a suitable starting point for a thorough investigation of positions 8 and 2. While position 8 of the purine scaffold can only bear a small substituent to maintain the inhibitory activity, position 2 is opened for extensive modification and can accommodate even substituted phenyl rings without the loss of PI4K IIIβ inhibitory activity. These empirical observations nicely correlate with the results of our docking study, which suggests that position 2 directs towards solution and can provide the necessary space for the interaction with remote residues of the enzyme, whereas the cavity around position 8 is strictly limited. The obtained compounds have also been subjected to antiviral screening against a panel of (+)ssRNA viruses.
Oxysterol-binding protein family I is the target of minor enviroxime-like compounds
J Virol 2013 Apr;87(8):4252-60.PMID:23365445DOI:10.1128/JVI.03546-12.
Enviroxime is an antipicornavirus compound that targets host phosphatidylinositol 4-kinase III beta (PI4KB) activity for its antipicornavirus activity. To date, several antipoliovirus (PV) compounds similar to enviroxime that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity, as well as enviroxime (designated major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB and was considered to belong to another group of enviroxime-like compounds (designated minor enviroxime-like compounds). In the present study, we performed a small interfering RNA (siRNA) sensitization assay targeting PI4KB-related genes and identified oxysterol-binding protein (OSBP) as a target of minor enviroxime-like compounds. Knockdown of OSBP and OSBP2 increased the anti-PV activities of AN-12-H5 and a newly identified minor enviroxime-like compound, T-00127-HEV2, and also to T-00127-HEV1 to a minor extent, in the cells. A ligand of OSBP, 25-hydroxycholesterol (25-HC), acted as a minor enviroxime-like compound. Minor enviroxime-like compounds induced relocalization of OSBP to the Golgi apparatus in cells. Treatment of the cells with major or minor enviroxime-like compounds suppressed the expression of genes (HMGCS1 and SQLE) in the SREBP/SCAP regulatory pathway and diminished endogenous phosphatidylinositol 4-phosphate (PI4P) at the Golgi apparatus. Our results suggested that minor enviroxime-like compounds are phenotypically identical to 25-HC and that major and minor enviroxime-like compounds suppress the production and/or accumulation of PI4P in PV-infected cells by targeting PI4KB and OSBP family I activities, respectively.
[Exploration for anti-enterovirus compounds and analysis on the mechanism of its inhibitory effect on virus infection]
Uirusu 2013;63(1):93-102.PMID:24769585DOI:10.2222/jsv.63.93.
Poliovirus (PV) is a small non-enveloped virus belonging to the family Picornaviridae, and is the causative agent of poliomyelitis. With established vaccines, the global eradication program for poliomyelitis is ongoing by the World Health Organization since 1988. In the eradication program, antivirals are anticipated to have some roles in the endgame and post-eradication era of PV. During our search for potent anti-PV compounds, we identified candidate compounds that are associated with a common resistance mutation in viral protein 3A similar to enviroxime (designated as enviroxime-like compounds). Recently, PIK93, an inhibitor of host phosphatidylinositol 4-kinase III beta (PI4KB), was identified as a potent anti-enterovirus compound (Hsu et al., Cell 141:799-811). We found that PIK93 is an enviroxime-like compound, and showed that T-00127-HEV1, which is a novel enviroxime-like compound identified in high-throughput screening, is a specific PI4KB inhibitor. We also showed that PI4KB is an enterovirus-specific host factor required for its viral RNA replication. Analysis of anti-enterovirus compounds would unravel novel host factors that could serve as promising antiviral targets of prophylaxis and therapy of the infection.
Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus
Bioorg Med Chem Lett 2013 Jul 1;23(13):3841-7.PMID:23726345DOI:10.1016/j.bmcl.2013.04.077.
We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.