Thienopyridone
目录号 : GC60364
Thienopyridone 是一种有效的选择性的肝再生磷酸酶 (PRL) 磷酸酶抑制剂，对于 PRL-1，PRL-2 和 PRL-3，IC50 值分别为 173 nM，277 nM 和 128 nM。Thienopyridone 对其他磷酸酶的影响很小。Thienopyridone 可诱导 p130Cas 裂解和细胞凋亡 (apoptosis)，并具有抗癌作用。
Cas No.:1018454-97-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Thienopyridone is a potent and selective phosphatase of regenerating liver (PRL) phosphatase inhibitor with IC50s of 173 nM, 277 nM and 128 nM for PRL-1, PRL-2, and PRL-3, respectively. Thienopyridone shows minimal effects on other phosphatases. Thienopyridone induces p130Cas cleavage and apoptosis and has anticancer effects[1].
Thienopyridone shows significant inhibition of tumor cell anchorage-independent growth in soft agar. The EC50 values of the Thienopyridone are 3.29 μM and 3.05 μM for RKO and HT-29 cells, respectively[1].Thienopyridone (1-75 μM; 24 hours; HeLa cells) treatment shows a dose-dependent down-regulation of total p130Cas in HeLa cells. Thienopyridone induces p130Cas and FAK cleavage leads to caspase-mediated cell apoptosis. Thienopyridone induces the cleavage of PARP and caspase-8[1].Thienopyridone (3.75-30 μM; 24 hours) significantly suppresses HUVEC migration but not proliferation[1]. Cell Viability Assay[1] Cell Line: RKO and HT-29 cells
[1]. Daouti S, et al. A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage. Cancer Res. 2008 Feb 15;68(4):1162-9.
| Cas No. | 1018454-97-1 | SDF | |
| Canonical SMILES | O=C1C(C=C(C2=CC=CC=C2)S3)=C3C(N)=CN1 | ||
| 分子式 | C13H10N2OS | 分子量 | 242.3 |
| 溶解度 | 储存条件 | ||
| 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 | 4.1271 mL | 20.6356 mL | 41.2712 mL |
| 5 mM | 0.8254 mL | 4.1271 mL | 8.2542 mL |
| 10 mM | 0.4127 mL | 2.0636 mL | 4.1271 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。
Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health
Curr Med Chem 2019;26(27):5207-5229.PMID:29623826DOI:10.2174/0929867325666180406120051.
Adenosine 5'-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside Thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.
Mechanism of Thienopyridone and iminothienopyridinedione inhibition of protein phosphatases
Medchemcomm 2019 Apr 5;10(5):791-799.PMID:31191869DOI:10.1039/c9md00175a.
Thienopyridone (TP) has been proposed as a selective inhibitor of phosphatases of regenerating liver (PRL or PTP4A). PRLs are dual specificity phosphatases that promote cancer progression and are attractive anticancer targets. TP and iminothienopyridinedione (ITP), a more potent derivative, were shown to be effective inhibitors but the mechanism of inhibition was not established. Here, we perform NMR experiments and in vitro phosphatase assays to show that TP and ITP inhibit protein phosphatases non-specifically through oxidation of the phosphatase catalytic cysteine. We demonstrate that TP and ITP are redox active compounds, inhibiting PRL-3 and multiple other PTPs through oxidation. They also catalyze the oxidation of thioredoxin-1 as well as small molecules, like TCEP, DTT, and glutathione. The reported selectivity of TP and ITP is likely due to the higher susceptibility of PRLs to oxidation. Thus, while TP and ITP effectively inhibit PRLs, their use for studying the cellular function of PRLs is problematic due to the likelihood of off-target effects.
Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor
Org Biomol Chem 2016 Jul 6;14(27):6398-402.PMID:27291491DOI:10.1039/c6ob00946h.
The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich Thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation. Analog 13 should become a valuable tool for further exploration of the role of PTP4A3 in tumor progression.
Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes
Chem Biol 2008 Nov 24;15(11):1220-30.PMID:19022182DOI:10.1016/j.chembiol.2008.10.005.
The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that plays a pivotal role in regulating cellular and whole-body metabolism. Activation of AMPK reverses many of the metabolic defects associated with obesity and type 2 diabetes, and therefore AMPK is considered a promising target for drugs to treat these diseases. Recently, the Thienopyridone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the beta subunit carbohydrate-binding module and residues from the gamma subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the beta1 subunit. Our findings highlight the regulatory role played by the beta subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator.
Structure and function of AMP-activated protein kinase
Acta Physiol (Oxf) 2009 May;196(1):3-14.PMID:19245650DOI:10.1111/j.1748-1716.2009.01977.x.
AMP-activated protein kinase (AMPK) regulates metabolism in response to energy demand and supply. AMPK is activated in response to rises in intracellular AMP or calcium-mediated signalling and is responsible for phosphorylating a wide variety of substrates. Recent structural studies have revealed the architecture of the alphabetagamma subunit interactions as well as the AMP binding pockets on the gamma subunit. The alpha catalytic domain (1-280) is autoinhibited by a C-terminal tail (313-335), which is proposed to interact with the small lobe of the catalytic domain by homology modelling with the MARK2 protein structure. Two direct activating drugs have been reported for AMPK, the Thienopyridone compound A769662 and PTI, which may activate by distinct mechanisms.