GSK 2830371Potent and selective allosteric inhibitor of Wip1 phosphatase CAS# 1404456-53-6 |
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Quality Control & MSDS
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| Cas No. | 1404456-53-6 | SDF | Download SDF |
| PubChem ID | 70983932 | Appearance | Powder |
| Formula | C23H29ClN4O2S | M.Wt | 461.02 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 51 mg/mL (110.62 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 5-[[(5-chloro-2-methylpyridin-3-yl)amino]methyl]-N-[(2S)-3-cyclopentyl-1-(cyclopropylamino)-1-oxopropan-2-yl]thiophene-2-carboxamide | ||
| SMILES | CC1=NC=C(C=C1NCC2=CC=C(S2)C(=O)NC(CC3CCCC3)C(=O)NC4CC4)Cl | ||
| Standard InChIKey | IVDUVEGCMXCMSO-FQEVSTJZSA-N | ||
| Standard InChI | InChI=1S/C23H29ClN4O2S/c1-14-19(11-16(24)12-25-14)26-13-18-8-9-21(31-18)23(30)28-20(10-15-4-2-3-5-15)22(29)27-17-6-7-17/h8-9,11-12,15,17,20,26H,2-7,10,13H2,1H3,(H,27,29)(H,28,30)/t20-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Potent and selective allosteric inhibitor of Wip1 phosphatase (IC50 = 6 nM). Exhibits selectivity for Wip1 over 21 other phosphatases. Increases phosphorylation of Wip1 substrates, including p53, Chk2, H2AX and ATM. Attenuates tumor cell growth in a variety of lymphoid cell lines. Also inhibits lymphoma xenograft growth in vivo. Potentiates growth inhibitory effects of MDM2 inhibition in cancer cell lines in a p53-dependent manner. Orally bioavailable. |
GSK 2830371 Dilution Calculator
GSK 2830371 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.1691 mL | 10.8455 mL | 21.691 mL | 43.3821 mL | 54.2276 mL |
| 5 mM | 0.4338 mL | 2.1691 mL | 4.3382 mL | 8.6764 mL | 10.8455 mL |
| 10 mM | 0.2169 mL | 1.0846 mL | 2.1691 mL | 4.3382 mL | 5.4228 mL |
| 50 mM | 0.0434 mL | 0.2169 mL | 0.4338 mL | 0.8676 mL | 1.0846 mL |
| 100 mM | 0.0217 mL | 0.1085 mL | 0.2169 mL | 0.4338 mL | 0.5423 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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GSK2830371 is a orally active, allosteric inhibitor of Wip1 phosphatase with IC50 of 6 nM.
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GSK-3beta Overexpression Alters the Dendritic Spines of Developmentally Generated Granule Neurons in the Mouse Hippocampal Dentate Gyrus.[Pubmed:28344548]
Front Neuroanat. 2017 Mar 10;11:18.
The dentate gyrus (DG) plays a crucial role in hippocampal-related memory. The most abundant cellular type in the DG, namely granule neurons, are developmentally generated around postnatal day P6 in mice. Moreover, a unique feature of the DG is the occurrence of adult hippocampal neurogenesis, a process that gives rise to newborn granule neurons throughout life. Adult-born and developmentally generated granule neurons share some maturational aspects but differ in others, such as in their positioning within the granule cell layer. Adult hippocampal neurogenesis encompasses a series of plastic changes that modify the function of the hippocampal trisynaptic network. In this regard, it is known that glycogen synthase kinase 3beta (GSK-3beta) regulates both synaptic plasticity and memory. By using a transgenic mouse overexpressing GSK-3beta in hippocampal neurons, we previously demonstrated that the overexpression of this kinase has deleterious effects on the maturation of newborn granule neurons. In the present study, we addressed the effects of GSK-3beta overexpression on the morphology and number of dendritic spines of developmentally generated granule neurons. To this end, we performed intracellular injections of Lucifer Yellow in developmentally generated granule neurons of wild-type and GSK-3beta-overexpressing mice and analyzed the number and morphologies of dendritic spines (namely, stubby, thin and mushroom). GSK-3beta overexpression led to a general reduction in the number of dendritic spines. In addition, it caused a slight reduction in the percentage, head diameter and length of thin spines, whereas the head diameter of mushroom spines was increased.
Transient Cerebral Ischemia Alters GSK-3beta and p-GSK-3beta Immunoreactivity in Pyramidal Neurons and Induces p-GSK-3beta Expression in Astrocytes in the Gerbil Hippocampal CA1 Area.[Pubmed:28349361]
Neurochem Res. 2017 Aug;42(8):2305-2313.
Glycogen synthase kinase 3beta (GSK-3beta) is a key downstream protein in the PI3K/Akt pathway. Phosphorylation of serine 9 of GSK-3beta (GSK-3beta activity inhibition) promotes cell survival. In this study, we examined changes in expressions of GSK-3beta and phosphorylation of GSK-3beta (p-GSK-3beta) in the gerbil hippocampal CA1 area after 5 min of transient cerebral ischemia. GSK-3beta immunoreactivity in the CA1 area was increased in pyramidal cells at 6 h after ischemia-reperfusion. It was decreased in CA1 pyramidal cells from 12 h after ischemia-reperfusion, and hardly detected in the CA1 pyramidal cells at 5 days after ischemia-reperfusion. p-GSK-3beta immunoreactivity was slightly decreased in CA1 pyramidal cells at 6 and 12 h after ischemia-reperfusion. It was significantly increased in these cells at 1 and 2 days after ischemia-reperfusion. Five days after ischemia-reperfusion, p-GSK-3beta immunoreactivity was hardly found in CA1 pyramidal cells. However, p-GSK-3beta immunoreactivity was strongly expressed in astrocytes primarily distributed in strata oriens and radiatum. In conclusion, GSK-3beta and p-GSK-3beta were significantly changed in pyramidal cells and/or astrocytes in the gerbil hippocampal CA1 area following 5 min of transient cerebral ischemia. This finding indicates that GSK-3beta and p-GSK-3beta are closely related to delayed neuronal death.
Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer's Disease.[Pubmed:28374012]
eNeuro. 2017 Mar 27;4(2). pii: eN-NWR-0149-16.
It is widely accepted that amyloid beta (Abeta) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer's disease (AD), yet little is known about the contribution of APP to intracellular signaling events preceding AD pathogenesis. The data presented here demonstrate that APP expression and neuronal exposure to oligomeric Abeta42 enhance Ras/ERK signaling cascade and glycogen synthase kinase 3 (GSK-3) activation. We find that RNA interference (RNAi)-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibits Ras-ERK signaling and GSK-3 activation, indicating that APP acts upstream of these signal transduction events. Both ERK and GSK-3 are known to induce hyperphosphorylation of tau and APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human AD brain samples showed increased expression of Ras, activation of GSK-3, and phosphorylation of APP and tau, which correlated with Abeta levels in the AD brains. Furthermore, treatment of primary rat neurons with Abeta recapitulated these events and showed enhanced Ras-ERK signaling, GSK-3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Abeta induces Thr668 phosphorylation on APP, which enhances APP proteolysis and Abeta generation, denotes a vicious feedforward mechanism by which APP and Abeta promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results, we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and that inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.
SLM, a novel carbazole-based fluorophore attenuates okadaic acid-induced tau hyperphosphorylation via down-regulating GSK-3beta activity in SH-SY5Y cells.[Pubmed:28359686]
Eur J Pharm Sci. 2017 Dec 15;110:101-108.
Phosphorylated tau dissociates from microtubules and aggregates to form neurofibrillary tangles resulting in neuronal toxicity and cognitive deficits. Attenuating tau hyperphosphorylation is considered as an effective therapeutic approach for Alzheimer's disease (AD). From our previous study, SLM, a carbazole-based fluorophore prevents Abeta aggregation, reduced glycogen synthase kinase-3beta (GSK-3beta) activity and tau hyperphosphorylation in triple transgenic mouse model of AD. However, the mechanism by which SLM attenuates tau hyperphosphorylation warrants further investigation. In the current study, we intend to evaluate the effects of SLM against okadaic acid (OA)-induced tau hyperphosphorylation and microtubules instability in human neuroblastoma (SH-SY5Y) cells. The results showed that, SLM reduced the OA-induced cell neurotoxicity and tau hyperphosphorylation in SH-SY5Y cells. SLM treatment down-regulated GSK-3beta activity. However, in the presence of GSK-3beta inhibitor (SB216763, 10muM), SLM treatment could not reduce GSK-3beta activity and tau hyperphosphorylation as compared with SB216763 treatment alone. Furthermore, SLM treatment also ameliorated OA-induced microtubules instability and cytoskeleton damage. Collectively, SLM attenuated OA-induced tau hyperphosphorylation via down-regulating GSK-3beta activity in SH-SY5Y cells. Therefore, this study supports SLM as a potential compound for AD and other tau pathology-related neurodegenerative disorders.
Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction.[Pubmed:24390428]
Nat Chem Biol. 2014 Mar;10(3):181-7.
Although therapeutic interventions of signal-transduction cascades with targeted kinase inhibitors are a well-established strategy, drug-discovery efforts to identify targeted phosphatase inhibitors have proven challenging. Herein we report a series of allosteric, small-molecule inhibitors of wild-type p53-induced phosphatase (Wip1), an oncogenic phosphatase common to multiple cancers. Compound binding to Wip1 is dependent on a 'flap' subdomain located near the Wip1 catalytic site that renders Wip1 structurally divergent from other members of the protein phosphatase 2C (PP2C) family and that thereby confers selectivity for Wip1 over other phosphatases. Treatment of tumor cells with the inhibitor GSK2830371 increases phosphorylation of Wip1 substrates and causes growth inhibition in both hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Oral administration of Wip1 inhibitors in mice results in expected pharmacodynamic effects and causes inhibition of lymphoma xenograft growth. To our knowledge, GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase.
