AZD8186
(Synonyms: 8-[(1R)-1-[(3,5-二氟苯基)氨基]乙基]-N,N-二甲基-2-(4-吗啉基)-4-氧代-4H-1-苯并吡喃-6-甲酰胺) 目录号 : GC12576
A PI3Kβ/δ inhibitor
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 | |
| 别名 | 8-[(1R)-1-[(3,5-二氟苯基)氨基]乙基]-N,N-二甲基-2-(4-吗啉基)-4-氧代-4H-1-苯并吡喃-6-甲酰胺 | ||
| 化学名 | (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 | ||
| 分子式 | C24H25F2N3O4 | 分子量 | 457.47 |
| 溶解度 | ≥ 45.7mg/mL in DMSO with ultrasonic | 储存条件 | Store at -20°C |
| 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 | 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 |
| 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。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet