PIK-93

PI3Kγ/PI4KIIIβ/PI3Kα inhibitor CAS# 593960-11-3

PIK-93

Catalog No. BCC2519----Order now to get a substantial discount!

Product Name & Size Price Stock
PIK-93:5mg $82.00 In stock
PIK-93:10mg $139.00 In stock
PIK-93:25mg $328.00 In stock
PIK-93:50mg $574.00 In stock
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Quality Control of PIK-93

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Chemical structure

PIK-93

3D structure

Chemical Properties of PIK-93

Cas No. 593960-11-3 SDF Download SDF
PubChem ID 6852167 Appearance Powder
Formula C14H16ClN3O4S2 M.Wt 389.88
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 150 mg/mL (384.73 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[5-[4-chloro-3-(2-hydroxyethylsulfamoyl)phenyl]-4-methyl-1,3-thiazol-2-yl]acetamide
SMILES CC1=C(SC(=N1)NC(=O)C)C2=CC(=C(C=C2)Cl)S(=O)(=O)NCCO
Standard InChIKey JFVNFXCESCXMBC-UHFFFAOYSA-N
Standard InChI InChI=1S/C14H16ClN3O4S2/c1-8-13(23-14(17-8)18-9(2)20)10-3-4-11(15)12(7-10)24(21,22)16-5-6-19/h3-4,7,16,19H,5-6H2,1-2H3,(H,17,18,20)
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.
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.
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.

Biological Activity of PIK-93

DescriptionPIK-93 is the first potent, synthetic inhibitor of PI3Kγ, PI4KIIIβ and PI3Kα with IC50 values of 16 nM, 19 nM and 39nM, respectively.
TargetsPI3KγPI4KIIIβPI3KαDNA-PKPI3Kδ  
IC5016 nM19 nM39 nM64 nM120 nM  

Protocol

Kinase Assay [1]
IC50 values are measured using a standard TLC assay for lipid kinase activity. Kinase reactions are performed by preparing areaction mixture containing kinase, PIK-93 (2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2), and freshly sonicated phosphatidylinositol (100 µg/mL). Reactions are initiated by the addition of ATP containing 10 µCi of γ-32P-ATP to a final concentration 10 or 100 µM, and allowed to proceed for 20 min at room temperature. For TLC analysis, reactions are then terminated by the addition of 105 µL 1N HCl followed by 160 µL CHCl3:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged, and the organic phase transferred to a new tube using a gel loading pipette tip precoated with CHCl3. This extract is spotted on TLC plates and developed for 3 hours-4 hours in a 65:35 solution of n-propanol:1M acetic acid. The TLC plates are then dried, exposed to a phosphorimager screen, and quantitated. Kinase activity is typically measured at 10-12 concentrations of PIK-93 representing two-fold dilutions from the highest concentration of 100 μM.

Cell Assay [1]
For actin staining, dHL60 cells are preincubated in suspension with PIK-93 or vehicle for 40 min, centrifuged for 5 min at 2000 rpm at room temperature in a J6-B centrifuge, resuspended in mHBSS containing the respective agent at the same concentration, allowed to stick to fibronectin-covered coverslips, and subjected to stimulation with a uniform concentration of 100 nM f-Met-Leu-Phe (fMLP) for 3 min. Cells are fixed in 3.7% PFA and stained with 10 units/mL rhodamine-phalloidin for 15 min.

References:
[1]. Knight ZA, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19;125(4):733-47. [2]. Van Keymeulen A, et al. To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front. J Cell Biol. 2006 Jul 31;174(3):437-45. [3]. Toth B, et al. Phosphatidylinositol 4-kinase IIIbeta regulates the transport of ceramide between the endoplasmic reticulum and Golgi. J Biol Chem. 2006 Nov 24;281(47):36369-77. [4]. Monet M, et al. Involvement of phosphoinositide 3-kinase and PTEN protein in mechanism of activation of TRPC6 protein in vascular smooth muscle cells. J Biol Chem. 2012 May 18;287(21):17672-81. [5]. 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.

PIK-93 Dilution Calculator

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PIK-93 Molarity Calculator

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Preparing Stock Solutions of PIK-93

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.5649 mL 12.8245 mL 25.6489 mL 51.2978 mL 64.1223 mL
5 mM 0.513 mL 2.5649 mL 5.1298 mL 10.2596 mL 12.8245 mL
10 mM 0.2565 mL 1.2824 mL 2.5649 mL 5.1298 mL 6.4122 mL
50 mM 0.0513 mL 0.2565 mL 0.513 mL 1.026 mL 1.2824 mL
100 mM 0.0256 mL 0.1282 mL 0.2565 mL 0.513 mL 0.6412 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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Background on PIK-93

PIK-93 is a potent and novel inhibitor of p110γ (PI3Kγ) and PI4KIIIβ (IC50= 16 nM and 19 nM, respectively).

PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) is a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. It plays a key role in PI3K/Akt/mTOR pathway.

Inhibition of PI3K via PIK-93 reduced the carbachol-activated translocation of TRPC6 to the plasma membrane and carbachol-activated net Ca(2+) entry into T6.11 cells. [1] PIK-93 also selectively inhibited the PI4KIIIβ enzyme, and siRNA-mediated down regulation of individual PI4-enzymes in COS-7 cells. [2] Furthermore, as a potent anti-PV compound, PIK93 targeted PI4Kβ to inhibit interaction of viral 3D polymerase and phosphatidylinositol 4-phosphate on the reorganized membrane vesicle for viral replication complex formation. [3] PIK93 also showed anti-PV with an EC50 of 0.14 μM for PV pseudovirus infection. [4]

References:
[1] Monet M, Francoeur N, Boulay G.  Involvement of phosphoinositide 3-kinase and PTEN protein in mechanism of activation of TRPC6 protein in vascular smooth muscle cells.  J Biol Chem. 2012 May 18;287(21):17672-81.
[2] Tóth B, Balla A, Ma H et al.  Phosphatidylinositol 4-kinase IIIbeta regulates the transport of ceramide between the endoplasmic reticulum and Golgi. J Biol Chem. 2006 Nov 24;281(47):36369-77.
[3] Hsu, N.  Y., et al. 2010. Viral reorganization of the secretory pathway generates distinct organelles for RNA replication.  Cell 141:799-811.
[4] Arita M, Kojima H, Nagano T 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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References on PIK-93

Involvement of phosphoinositide 3-kinase and PTEN protein in mechanism of activation of TRPC6 protein in vascular smooth muscle cells.[Pubmed:22493444]

J Biol Chem. 2012 May 18;287(21):17672-81.

TRPC6 is a cation channel in the plasma membrane that plays a role in Ca(2+) entry after the stimulation of a G(q)-protein-coupled or tyrosine-kinase receptor. TRPC6 translocates to the plasma membrane upon stimulation and remains there as long as the stimulus is present. However, the mechanism that regulates the trafficking and activation of TRPC6 are unclear. In this study we showed phosphoinositide 3-kinase and its antagonistic phosphatase, PTEN, are involved in the activation of TRPC6. The inhibition of PI3K by PIK-93, LY294002, or wortmannin decreased carbachol-induced translocation of TRPC6 to the plasma membrane and carbachol-induced net Ca(2+) entry into T6.11 cells. Conversely, a reduction of PTEN expression did not affect carbachol-induced externalization of TRPC6 but increased Ca(2+) entry through TRPC6 in T6.11 cells. We also showed that the PI3K/PTEN pathway regulates vasopressin-induced translocation of TRPC6 to the plasma membrane and vasopressin-induced Ca(2+) entry into A7r5 cells, which endogenously express TRPC6. In summary, we provided evidence that the PI3K/PTEN pathway plays an important role in the translocation of TRPC6 to the plasma membrane and may thus have a significant impact on Ca(2+) signaling in cells that endogenously express TRPC6.

Mitigating Motor Neuronal Loss in C. elegans Model of ALS8.[Pubmed:28912432]

Sci Rep. 2017 Sep 14;7(1):11582.

ALS8 is a late-onset familial autosomal dominant form of Amyotrophic Lateral Sclerosis (ALS) caused by a point mutation (P56S) in the VAPB gene (VAMP associated protein isoform B). Here, we generated two C. elegans models of the disease: a transgenic model where human VAPB wild-type (WT) or P56S mutant was expressed in a subset of motor neurons, and a second model that targeted inducible knockdown of the worm's orthologue, vpr-1. Overexpression of human VAPB in DA neurons caused a backward locomotion defect, axonal misguidance, and premature neuronal death. Knockdown of vpr-1 recapitulated the reduction in VAPB expression associated with sporadic cases of human ALS. It also caused backward locomotion defects as well as an uncoordinated phenotype, and age-dependent, progressive motor neuronal death. Furthermore, inhibiting phosphatidylinositol-4 (PtdIns 4)-kinase activity with PIK-93 reduced the incidence of DA motor neuron loss and improved backward locomotion. This supports the loss of VAPB function in ALS8 pathogenesis and suggests that reducing intracellular PtdIns4P might be an effective therapeutic strategy in delaying progressive loss of motor neurons.

Description

PIK-93 is the first potent, synthetic PI4K (PI4KIIIβ) inhibitor with IC50 of 19 nM, and also inhibits PI3Kγ and PI3Kα with IC50 of 16 nM and 39 nM, respectively.

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