Pilaralisib (XL147; SAR245408) is a potent and highly selective class IPI3Ks inhibitor withIC₅₀s of 39 nM, 383 nM, 23 nM and 36 nM forPI3Kα,PI3Kβ,PI3Kγ, andPI3Kδ.

Pilaralisib (XL147) displays potent inhibitory activity against Class I PI3K isoforms p110α, p110δ, and p110γ, with IC₅₀s of 39, 36, and 23 nM, respectively. Pilaralisib (XL147) is less potent against the remaining Class I isoform, p110β, with an IC₅₀value of 383 nM. The IC₅₀value for inhibition of PI3Kα by Pilaralisib (XL147) is determined at various concentrations of ATP, revealing XL147 to be an ATP-competitive inhibitor with an equilibrium inhibition constant (K_i) value of 42 nM. Pilaralisib (XL147) has relatively weak inhibitory activity toward the class III PI3K vacuolar sorting protein 34 (VPS34; IC₅₀value of ~7.0 M) and the PI3K-related DNA-dependent protein kinase (DNA-PK; IC₅₀value of 4.75 μM). In an mTOR kinase immunoprecipitation assay using cell lysates, Pilaralisib (XL147) does not inhibit mTOR activity toward the physiologic substrate protein eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1; IC₅₀>15 μM). Consistent with its inhibitory activity against purified PI3K proteins, Pilaralisib (XL147) inhibits EGF-induced PIP₃production in PC-3 and MCF7 cells in serum-free medium with IC₅₀s of 220 and 347 nM, respectively. The ability of Pilaralisib (XL147) to inhibit phosphorylation of key signaling proteins downstream of PI3K is examined by assessing its effects on EGF-stimulated phosphorylation of AKT and on nonstimulated phosphorylation of S6 in PC-3 cells in serum-free media by cell-based ELISA. Pilaralisib (XL147) inhibits these activities with IC₅₀s of 477 and 776 nM, respectively^[1].

The ability of Pilaralisib (XL147) to inhibit this endogenous phosphorylation of AKT, p70S6K, and S6 is examined following a single oral dose of 10, 30, 100, or 300 mg/kg. The tumors are harvested 4, 24, or 48 hours postdose and homogenized in lysis buffer. Tumor lysates from each animal (n=4) are then pooled for each group and analyzed for levels of total and phosphorylated AKT, p70S6K, and S6 by Western immunoblotting. Administration of Pilaralisib (XL147) causes a dose-dependent decrease in phosphorylation of AKT, p70S6K, and S6 in the tumors, reaching a maximum of 81% inhibition of AKT phosphorylation at 300 mg/kg at 4 hours. The dose-response relationships derived from the 4-hour time point predict 50% inhibition of AKT, p70S6K, and S6 phosphorylation at doses of approximately 100 mg/kg (pAKT^T308), 54 mg/kg (pAKT^S473), 71 mg/kg (p-p70S6K), and 103 mg/kg (pS6). The inhibition of AKT, p70S6K, and S6 phosphorylation in MCF7 tumors following a 100 mg/kg dose of Pilaralisib (XL147) is maximal at 4 hours, reaching 55% to 75%; however, the level of inhibition decreased to 8% to 45% by 24 hours, and only minimal or no inhibition was evident by 48 hours. Following a 300 mg/kg dose of Pilaralisib (XL147), inhibition is also maximal at 4 hours (65%-81%). However, in contrast with the 100 mg/kg dose, inhibition at 24 hours (51%-78%) is almost comparable with that seen at 4 hours, and partial inhibition (25%-51%) persisted through 48 hours^[1].

541.02

Solid

C₂₅H₂₅ClN₆O₄S

934526-89-3

Room temperature in continental US; may vary elsewhere.

DMSO : ≥ 100 mg/mL(184.84 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℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 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    40%PEG300   5%Tween-80   45% saline

  Solubility: ≥ 2.5 mg/mL (4.62 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (4.62 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% (20%SBE-β-CDin saline)

  Solubility: 2.5 mg/mL (4.62 mM); Suspended solution; Need ultrasonic

  此方案可获得 2.5 mg/mL (4.62 mM) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。

  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 μL20% 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