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).

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.

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.

457.47

C₂₄H₂₅F₂N₃O₄

1627494-13-6

Room temperature in continental US; may vary elsewhere.

DMSO : ≥ 35 mg/mL (76.51 mM)

* “≥” means soluble, but saturation unknown.

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。

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。

• [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.

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.

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.

• [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.