PF-4989216 is a potent and selective PI3Kα inhibitor with a K_i of 0.6 nM.

PF-4989216 (Compound 10) has excellent PI3Kα K_i (0.6 nM), good cellular potency (S473 IC₅₀=79 nM), and good selectivity against mTOR (mTOR K_i=1440 nM). PF-4989216 has PI3Kα K_i less than 1 nM and mTOR K_i more than 1 μM. PF-4989216 also has excellent selectivity over 40 other kinases, and no major CYP inhibitions are observed. Less than 30% inhibition is observed in 1A2, 2C9, 2D6, and 3A4 CYP enzymes at 3 μM^[1]. The toxicity of PF-4989216 in several drug-sensitive and MDR cancer cell lines, including cells overexpressing ABCB1 or ABCG2, and in HEK293 cells transfected with human ABCB1 or ABCG2 is determined. PF-4989216 inhibits human colon carcinoma S1 cell line and ABCG2-overexpressing subline S1-M1-80 with IC₅₀s of 1.11±0.09 and 6.79±1.00 uM, respectively. PF-4989216 inhibits human breast carcinoma MCF-7 and ABCG2-overexpressing sublines MCF7-FLV1000 and MCF7-AdVp3000 IC₅₀s of 2.30±0.68, 23.26±2.94 and 62.57±5.46 uM, respectively. PF-4989216 inhibits pcDNA-HEK293, ABCB1-transected MDR19-HEK293, ABCG2-tranfected R482-HEK293 cells with IC₅₀s of 0.44±0.05, 0.38±0.06 and 5.05±0.89 uM, respectively^[2].

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.

PF-4989216 (Compound 10) is dosed orally in our in vivo antitumor model, PI3K driven NCI-H1975 xenograft tumors. PF-4989216 demonstrates dose responsive tumor growth inhibitory activity from 25 to 200 mg/kg in QD oral dosing^[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.

380.40

C₁₈H₁₃FN₆OS

1276553-09-3

Room temperature in continental US; may vary elsewhere.

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

In Vitro: 

DMSO : ≥ 29 mg/mL (76.24 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。

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    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 2.5 mg/mL (6.57 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (6.57 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 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

• 2.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 2.5 mg/mL (6.57 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (6.57 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 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [1]. Liu KK, et al. Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity. ACS Med Chem Lett. 2011 Sep 19;2(11):809-813.

MTT and CCK-8 assays are performed to determine the general sensitivities of cells to the tested drugs. The human colon carcinoma S1 cell line and ABCG2-overexpressing subline S1-M1-80 are treated with PF-4989216 (0.1, 1 and 10 μM). The human breast carcinoma MCF-7 and ABCG2-overexpressing sublines MCF7-FLV1000 and MCF7-AdVp3000 are treated with PF-4989216 (0.1, 1, 10 and 100 μM).The parental HEK293 and ABCG2-tranfected R482-HEK293 cells are treated with PF-4989216 (0.01, 0.1, 1 and 10 μM). For the reversal of cytotoxicity assays, PF-4989216 or Ko143 or Lapatinib at a nontoxic concentration is added into the cytotoxicity assay, and the extent of reversal is then calculated^[2].

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]
For animal studies, 6-8 week old nu/nu athymic female mice are used. Tumors are established by injecting 2×10⁶ cells suspended 1:1 (v/v) with reconstituted basement membrane. For tumor growth inhibition studies, mice with established tumors of ~150 mm³ are randomized. PF-4989216 (Compound 10) is dosed orally (25, 50, 100 and 200 mg/kg) in a mouse PI3K driven NCI-H1975 xenograft tumor model. Tumor dimensions are measured with vernier calipers, and tumor volumes are calculated. Tumor growth inhibition percentage (TGI %) is calculated.

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]. Liu KK, et al. Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity. ACS Med Chem Lett. 2011 Sep 19;2(11):809-813.