AZD8186 |
| カタログ番号GC12576 |
AZD8186 は PI3K 阻害剤であり、PI3Kα (IC50=35 nM) および PI3Kγ (IC50=675 nM) よりも選択的に PI3Kβ (IC50=4 nM) および PI3Kδ (IC5050=12 nM) を強力に阻害します。
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1627494-13-6
Sample solution is provided at 25 µL, 10mM.
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Description:
IC50: 0.003 μM for PI3Kβ and 0.017 μM for PI3Kδ
The PI3K-Akt signaling pathway plays a critical role in cell growth, proliferation, motility, and survival. In human cancer, this pathway is activated by several mechanisms, including somatic mutations, deletions, and amplifications. Class I PI3Ks are further divided into class IA enzymes (PI3Kα, PI3Kβ, and PI3Kδ) and class IB enzymes (PI3Kγ). AZD8186 is a potent and selective inhibitor of PI3Kβ and PI3Kδ.
In vitro: AZD8186 gave potent inhibition of p-Akt in cells sensitive to PI3Kβ inhibition and in cells sensitive to PI3Kδ inhibition but not to cells sensitive to PI3Kα inhibition. The overall kinase selectivity of AZD8186 was evaluated in several panels of recombinant protein and lipid kinase assays. 13 did not show significant activity against a panel of 59 protein kinases tested at 1 μM [1].
In vivo: The antitumor activity of AZD8186 was evaluated in the PTEN deficient PC3 prostate tumor xenograft model in nude mice, either at 100 mg/kg b.i.d. without ABT coadministration, or at 60, 30, and 10 mg/mg b.i.d. with ABT coadministration. Higher inhibition was seen in the 60 and 30 mg/kg groups with ABT coadministration than in the 100 mg/kg group without ABT coadministration [1].
Clinical trial: AZD8186 was selected as a clinical candidate for treatment of PTENdeficient cancers and has recently entered phase I clinical trials [2].
Reference:
[1] Barlaam B, Cosulich S, Degorce S, Fitzek M, Green S, Hancox U, Lambert-van der Brempt C, Lohmann JJ, Maudet M, Morgentin R, Pasquet MJ, Péru A, Plé P, Saleh T, Vautier M, Walker M, Ward L, Warin N. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl -2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers. J Med Chem. 2015 Jan 22;58(2):943-62.
[2] https://clinicaltrials. gov/ct2/show/NCT01884285?term=AZD8186&rank=1
Cell experiment: | Cells are exposed to AZD8186 at concentrations ranging from 3 to 0.01 μM for 2 hours. Cells are then lysed on ice with a buffer containing 25 mM Tris/HCL pH6.8, 3 mM EDTA, 3 mM EGTA, 50 mM NaF, 2 mM sodium orthovanadate, 270 mM sucrose, 10 mM β-glycerophosphate, 5 mM sodium pyrophosphate, and 0.5% Triton X-100 and protease and phosphatase inhibitors. Lysates are diluted with sample loading buffer, separated on 4% to 12% Bis-Tris Novex gels, transferred onto nitrocellulose membranes, and probed with primary antibodies overnight. After a washing step, membranes are incubated with HRP-tagged secondary antibodies and visualized[1]. |
Animal experiment: | Mice[1] The female CB17 SCID mice ages 6 to 8 weeks are used. HID28 in vivo experiments are performed under contract by Xentech, HID28 tumor fragments (approximately 40 mm3) from donor animals are aseptically implanted subcutaneously in at the level of the interscapular region. Outbred athymic (nu/nu) male mice (HSD: Athymic Nude-Foxn1nu) weighing 18 to 25 g. For all animals studies groups are powered with a minimum of 8 animals per group. AZD8186 is generally formulated once weekly as a suspension in HPMC/Tween and dosed once or twice daily (0 and 6-8 hours). AZD8186 is formulated once weekly either alone in 10% DMSO/60% tri-ethylene glycol (TEG)/30% water for injection (WFI) or in the presence of ABT at 10 mg/mL. For twice daily dosing (0 and 6-8 hours), AZD8186 is co-dosed with ABT at 0 hours and administered alone as the single formulation at 6 to 8 hours. RP-56976 is formulated fresh in physiologic saline at 1.5 mg/mL and dosed as a single i.v. bolus dose at a rate of 0.1 mL/10 g on day 0, 24 hours before the administration of AZD8186. |
References: [1]. Hancox U, et al. Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with RP-56976. Mol Cancer Ther. 2015 Jan;14(1):48-58. | |
| Cas No. | 1627494-13-6 | SDF | |
| Chemical Name | (R)-8-(1-((3,5-difluorophenyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide | ||
| Canonical SMILES | C[C@](NC1=CC(F)=CC(F)=C1)([H])C2=C3C(C(C=C(O3)N4CCOCC4)=O)=CC(C(N(C)C)=O)=C2 | ||
| Formula | C24H25F2N3O4 | M.Wt | 457.47 |
| 溶解度 | ≥ 45.7mg/mL in DMSO with ultrasonic | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1859 mL | 10.9297 mL | 21.8594 mL |
| 5 mM | 0.4372 mL | 2.1859 mL | 4.3719 mL |
| 10 mM | 0.2186 mL | 1.093 mL | 2.1859 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 37 reference(s) in Google Scholar.)
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