AZD8186

上海金畔生物科技有限公司为生命科学和医药研发人员提供生物活性分子抑制剂、激动剂、特异性抑制剂、化合物库、重组蛋白,专注于信号通路和疾病研究领域。

AZD8186  纯度: 99.97%

AZD8186 是一种 PI3K 抑制剂,抑制 PI3Kβ (IC5050=4 nM),PI3Kδ (IC5050=12 nM),PI3Kα (IC50=35 nM) 和 PI3Kγ (IC50=675 nM)。

AZD8186

AZD8186 Chemical Structure

CAS No. : 1627494-13-6

规格 价格 是否有货 数量
Free Sample (0.1-0.5 mg)   Apply now  
10 mM * 1 mL in DMSO ¥1210 In-stock
5 mg ¥1100 In-stock
10 mg ¥1800 In-stock
50 mg ¥5800 In-stock
100 mg ¥9100 In-stock
200 mg   询价  
500 mg   询价  

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生物活性

AZD8186 is a PI3K inhibitor, which potently inhibits PI3Kβ (IC50=4 nM) and PI3Kδ (IC5050=12 nM) with selectivity over PI3Kα (IC50=35 nM) and PI3Kγ (IC50=675 nM).

IC50 & Target[1]

PI3Kβ

4 nM (IC50)

PI3Kδ

12 nM (IC50)

PI3Kα

35 nM (IC50)

PI3Kγ

675 nM (IC50)

体外研究
(In Vitro)

AZD8186 is a potent inhibitor of PI3Kβ with additional activity versus the PI3Kδ isoform. Tight-binding kinetics of AZD8186 means biochemical assays underestimate the absolute selectivity profile for PI3Ks. In a broad panel of protein and lipid kinase assays selectivity for PI3Kβ and δ is >100-fold versus 74 protein and lipid kinases. At 10 μM, AZD8186 had no significant binding to 442 other kinases in a KinomeScan screen. AZD8186 shows selectivity for PI3K family kinases, no other off-target activity is detected. In the PTEN-null line, MDA-MB-468 AZD8186 inhibits PI3Kβ-dependent activation of pAKT (Ser473) with an IC50 value of 3 nM. Potency in the PIK3CA-mutant line BT474c is 752 nM demonstrating selectivity for PI3Kβ over PI3Kα. IgM mediated stimulation of B cells results in phosphorylation of AKT through activation of PI3Kδ. AZD8186 inhibits IgM-stimulated phosphorylation of pAKT (Ser473) activation in JEKO cells with an IC50 value of 17 nM. In cell proliferation assays, AZD8186 inhibits proliferation of MDA-MB-468 cells with a GI50 value of 65 nM, IgM stimulated JEKO cell growth with an IC50 value of 228 nM. It only inhibited BT474c cell growth with an IC50 value of 1.981 μM consistent with its selectivity for PI3Kβ over PI3Kα[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

体内研究
(In Vivo)

To assess single-agent efficacy of AZD8186 in vivo, antitumor activity is assessed in the PTEN-null TNBC models HCC70 and MDA-MB-468, and the prostate models PC3 and HID28. At 50 and 25 mg/kg twice a day, AZD8186 inhibits the growth of all four models. At 25 and 50 mg/kg, HCC70 is inhibited at 62% (P<0.001) and 85% (P<0.001), respectively, MDA-MB-468 is inhibited at 47% (P<0.001) and 76% (P<0.001), respectively, at end at of study, with regression early in the study. Efficacy in the PTEN-null prostate model, PC3 is less pronounced with 25 and 50 mg/kg giving maximal growth inhibition of 59% (P<0.001) and 64% (P<0.001), respectively. In contrast, AZD8186 gives 79% (P<0.001) growth inhibition in the PTEN-null prostate explant model HID28. In mouse, AZD8186 has a short half-life delivering a PK profile that results in intermittent cover over a 24 hours dosing interval. To increase the time of exposure, animals bearing PC3 tumors are co-dosed with AZD8186 in the presence of the Cyt P450 inhibitor ABT, which results in significantly increased exposure. This also increased the efficacy in the PC3 model with 86% (P<0.005) reduction in tumor growth achieved with 30 mg/kg AZD8186+ABT[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial

分子量

457.47

Formula

C24H25F2N3O4

CAS 号

1627494-13-6

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
溶解性数据
In Vitro: 

DMSO : ≥ 35 mg/mL (76.51 mM)

* “≥” means soluble, but saturation unknown.

配制储备液
浓度 溶剂体积 质量 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 1.0930 mL 2.1859 mL

*

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, 6 months; -20°C, 1 month。-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。

In Vivo:

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液,再依次添加助溶剂:

——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用; 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶

  • 1.

    请依序添加每种溶剂: 10% DMSO/60% tri-ethylene glycol (TEG)/30% water

    Solubility: 15 mg/mL (32.79 mM); Clear solution; Need ultrasonic

  • 2.

    请依序添加每种溶剂: 5% DMSO    40% PEG300    5% Tween-80    50% saline

    Solubility: ≥ 2.75 mg/mL (6.01 mM); Clear solution

  • 3.

    请依序添加每种溶剂: 5% DMSO    95% (20% SBE-β-CD in saline)

    Solubility: ≥ 2.75 mg/mL (6.01 mM); Clear solution

  • 4.

    请依序添加每种溶剂: 10% DMSO    40% PEG300    5% Tween-80    45% saline

    Solubility: ≥ 2.08 mg/mL (4.55 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (4.55 mM,饱和度未知) 的澄清溶液。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。

    将 0.9 g 氯化钠,完全溶解于 100 mL ddH₂O 中,得到澄清透明的生理盐水溶液

  • 5.

    请依序添加每种溶剂: 10% DMSO    90% (20% SBE-β-CD in saline)

    Solubility: ≥ 2.08 mg/mL (4.55 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (4.55 mM,饱和度未知) 的澄清溶液。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。

    将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中,再用生理盐水定容至 10 mL,完全溶解,澄清透明
  • 6.

    请依序添加每种溶剂: 10% DMSO    90% corn oil

    Solubility: ≥ 2.08 mg/mL (4.55 mM); Clear solution

    此方案可获得 ≥ 2.08 mg/mL (4.55 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。

    以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。

*以上所有助溶剂都可在 上海金畔生物科技有限公司 网站选购。
参考文献
  • [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.

Cell Assay
[1]

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].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

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.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

参考文献
  • [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.

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