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PI4KIII beta inhibitor 3

PI4KIII beta inhibitor CAS# 1245319-54-3

PI4KIII beta inhibitor 3

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Chemical structure

PI4KIII beta inhibitor 3

3D structure

Chemical Properties of PI4KIII beta inhibitor 3

Cas No. 1245319-54-3 SDF Download SDF
PubChem ID 46916382 Appearance Powder
Formula C22H22N8OS M.Wt 446.53
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble in DMSO
Chemical Name 4-(5-amino-2-pyridin-3-yl-[1,3]thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-methylphenyl)piperazine-1-carboxamide
SMILES CC1=CC=C(C=C1)NC(=O)N2CCN(CC2)C3=C4C(=NC(=N3)N)SC(=N4)C5=CN=CC=C5
Standard InChIKey UWTRKIJAGTTXNM-UHFFFAOYSA-N
Standard InChI InChI=1S/C22H22N8OS/c1-14-4-6-16(7-5-14)25-22(31)30-11-9-29(10-12-30)18-17-20(28-21(23)27-18)32-19(26-17)15-3-2-8-24-13-15/h2-8,13H,9-12H2,1H3,(H,25,31)(H2,23,27,28)
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 PI4KIII beta inhibitor 3

DescriptionPI4KIII beta inhibitor 3 is a novel and high effective ΡΙ4ΚΙΙΙβ inhibitor with IC50 of 5.7 nM.In Vitro:PI4KIII beta inhibitor 3 is a PI4KIII inhibitor extracted from patent WO/2013034738 A1, the compound of formula 3, has an IC50 of 5.7 nM. PI4KIII beta inhibitor 3 exerts significant immunosuppressive activity, with IC50 value of 3 nM in the mixed lymphocyte reaction (MLR) assay. PI4KIII beta inhibitor 3 inhibits IL2 and IFNy secretion with IC50 values of less than InM in each case. Thus, PI4KIII beta inhibitor 3 is shown to be as effective at inhibiting IL2 and IFNy secretion as conventional immunosuppressants such as cyclosporine A. IC50 on IFNy and IL-2 release of Cyclosporine A are 2nM and less than 1 nM respectively[1].In Vivo:PI4KIII beta inhibitor 3 (40 mg/kg per day, n=12) is able to delay the onset of arthritic symptoms and also to decrease symptom severity in a preventive model of arthritis compared to a vehicle control (MC 1%, n=12). PI4KIII beta inhibitor 3 reduces the anti-CII IgG titre and histological scores in the collagen-induced arthritis mouse model. Oral administration of PI4KIII beta inhibitor 3 results in prolonged graft survival in 3 out of 6 grafts in each group at day 30. Several grafts continued beating after withdrawal of the treatment (up to 60 days), indicating the induction of a certain type of graft tolerance. To evaluate the operational tolerance phenotype, animals with functional graft at day 60 are challenged with a second graft from the same donor strain or from a third party. No treatment is applied. The second grafts from the third party are rejected at day 8 (n=2) whereas second grafts from the same donor strain are functional for more than 90 days (n=2)[1].

References:
[1]. Jean Herman, et al. Autoimmune and inflammatory disorder therapy. From PCT Int. Appl. (2013), WO 2013034738 A1

Protocol

Animal Administration [1]
Mice[1] DBA1 male mice, 8-10 weeks old, are distributed in 2 groups according to the treatment. Twelve animals received daily treatment with vehicle (1% methylcellulose), twelve others receive PI4KIII beta inhibitor 3 at 40 mg/kg/d in 1% methylcellulose. The treatment initiation started the day before the intradermal injection at the base of the tail of 100 μg of emulsified chicken collagen II in presence of complete Freund adjuvant and added heat-killed Mycobacterium butyricum. Daily inspection of the mice is performed to weight animals and quantify disease score according to the following scale (score 0: normal; score 1 : redness and/or swelling in one joint; score 2: redness and/or swelling in more than one joint; score 3: redness and/or swelling in the entire paw; score 4: deformity and/or ankylosis). On the day of sacrifice (day 42) serum are collected and anti-collagen II antibody titers are determined by ELISA. Joints are harvested, fixed in 6% paraformaldehyde, decalcified in formic acid 6% for 48 h, sliced and stained by hematoxylin and eosin staining. Hyperplasia of the synovium, infiltration of mono and polymorphonuclear cells and pannus formation parameters are scored blindly.

References:
[1]. Jean Herman, et al. Autoimmune and inflammatory disorder therapy. From PCT Int. Appl. (2013), WO 2013034738 A1

PI4KIII beta inhibitor 3 Dilution Calculator

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PI4KIII beta inhibitor 3 Molarity Calculator

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Preparing Stock Solutions of PI4KIII beta inhibitor 3

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2395 mL 11.1975 mL 22.3949 mL 44.7898 mL 55.9873 mL
5 mM 0.4479 mL 2.2395 mL 4.479 mL 8.958 mL 11.1975 mL
10 mM 0.2239 mL 1.1197 mL 2.2395 mL 4.479 mL 5.5987 mL
50 mM 0.0448 mL 0.2239 mL 0.4479 mL 0.8958 mL 1.1197 mL
100 mM 0.0224 mL 0.112 mL 0.2239 mL 0.4479 mL 0.5599 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 PI4KIII beta inhibitor 3

Description: IC50 Value: 5.7 nM[1] PI4KIII beta inhibitor 3, 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p-tolylpiperazine-1-carboxamide, is a novel and high effective PI4KIII beta inhibitor. in vitro: The most effective test compound, the compound of formula 3 (PI4KIII beta inhibitor 3), inhibited IL2 and IFNy secretion with IC50 values of less than 1 nM in each case. Thus, the compound of formula (3) was shown to be as effective at inhibiting IL2 and IFNy secretion as conventional immunosuppressants such as cyclosporine A. IC50 on IFNy and IL-2 release of Cyclosporine A are 2nM and less than 1 nM respectively [1]. in vivo: Twelve animals received daily treatment with vehicle (1%methylcellulose), twelve others received PI4KIII beta inhibitor 3 at 40 mg/kg/d in 1% methylcellulose [1]. Clinical trial: N/A

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References on PI4KIII beta inhibitor 3

Interplay of genes in plant-pathogen interactions: In planta expression and docking studies of a beta 1,3 glucanase gene from Piper colubrinum and a glucanase inhibitor gene from Phytophthora capsici.[Pubmed:27924129]

Physiol Mol Biol Plants. 2016 Oct;22(4):567-573.

Oomycete pathogen, Phytophthora capsici is devastating for black pepper (Piper nigrum L.) and causes foot rot disease at all stages of plant growth. Phytophthora secretes a glucanase inhibitor protein (GIP), which is capable of inhibiting defence proteins like endoglucanases. In this particular study Quantitative PCR analysis, molecular docking studies and analysis of sequences of Glucanase inhibitor protein and beta-1,3 glucanse genes were done mainly depending on the data derived from Phytophthora capsici whole genome sequencing and Piper colubrinum RNA-sequencing (RNA-Seq). Amino acid sequence length of GIP gene from P. capsici was about 353 amino acids and that of glucanase pcEGase gene from P. colubrinum was about 312 amino acids. GIP gene from P. capsici showed high level of expression at early hours of the inoculation time period and pcEGase gene showed high level of expression at 16 hpi. High level of expression of pcEGase gene at 16 hpi is an indication that the GIP gene is successfully inhibited by the glucanase protein from the plant. Moreover insilico studies gave some hint on the importance of certain sites on the surfaces of both interacting proteins that might be having a role in binding of the two proteins and subsequent reactions thereof. Insilico analysis also conclusively proved that inhibition of glucanase inhibitor protein is mainly caused by recognition of an arginine as well as an isoleucine residue during the interaction of the two proteins.

Discovery of a Phosphoinositide 3-Kinase (PI3K) beta/delta Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kbeta Potency in a PI3Kdelta-Selective Template by Targeting Nonconserved Asp856.[Pubmed:28106991]

J Med Chem. 2017 Feb 23;60(4):1555-1567.

Phosphoinositide 3-kinase (PI3K) beta signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kbeta/delta inhibitors in which PI3Kbeta potency was built in a PI3Kdelta-selective template. This work led to the discovery of a highly selective PI3Kbeta/delta inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.[Pubmed:27933948]

J Med Chem. 2016 Dec 8;59(23):10435-10450.

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Abeta levels in rats and nonhuman primates and CSF Abeta levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

Na(+)/H(+) exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous beta-globin knockout thalassemic mice.[Pubmed:27995414]

Mol Cell Biochem. 2017 Mar;427(1-2):201-208.

Recent investigation has shown that the liver-derived iron-regulating hormone, hepcidin, can potentiate intestinal calcium absorption in hemizygous beta-globin knockout thalassemic (BKO) mice. Since the upregulation of Fe(2+) and H(+) cotransporter, divalent metal transporter (DMT)-1, has been shown to correlate with thalassemia-induced intestinal calcium absorption impairment, the inhibition of the apical Na(+)/H(+) exchanger (NHE)-3 that is essential for cytoplasmic pH regulation and transepithelial sodium absorption was hypothesized to negatively affect hepcidin action. Herein, the positive effect of hepcidin on the duodenal calcium transport was evaluated using Ussing chamber technique. The results showed that BKO mice had lower absorptive surface area and duodenal calcium transport than wild-type mice. Besides, paracellular transport of zinc in BKO mice was compromised. Hepcidin administration completely restored calcium transport. Since this hepcidin action was totally abolished by inhibitors of the basolateral calcium transporters, Na(+)/Ca(2+) exchanger (NCX1) and plasma membrane Ca(2+)-ATPase (PMCA1b), the enhanced calcium flux potentially occurred through the transcellular pathway rather than paracellular pathway. Interestingly, the selective NHE3 inhibitor, 100 nM tenapanor, markedly inhibited hepcidin-enhanced calcium transport. Accordingly, hepcidin is one of the promising therapeutic agents for calcium malabsorption in beta-thalassemia. It mainly stimulates the transcellular calcium transport across the duodenal epithelium in an NHE3-dependent manner.

Description

PI4KIII beta inhibitor 3 is a novel and high effective ΡΙ4ΚΙΙΙβ inhibitor with IC50 of 5.7 nM.

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