LY2874455 is a pan-FGFR inhibitor with IC₅₀s of 2.8, 2.6, 6.4, 6 nM for FGFR1, FGFR2, FGFR3, FGFR4, respectively.

LY2874455 potently inhibits the Erk phosphorylation induced by FGF2 and FGF9 in both cell lines in a dose-dependent manner, with average IC₅₀ values of 0.3 to 0.8 nM. LY2874455 indeed inhibits FGFR2 phosphorylation in SNU-16 and KATO-III cells, with estimated IC₅₀ values of 0.8 and 1.5 nM, respectively. In addition, LY2874455 inhibits the phosphorylation of FRS2, an immediate downstream target of FGFR in these cell lines, again with a similar potency of 0.8 to 1.5 nM. Together, these results suggest that LY2874455 inhibits FGFR in the cell. The relative IC₅₀ values of LY2874455 for KMS-11, OPM-2, L-363, and U266 cells are determined to be 0.57, 1.0, 60.4, and 290.7 nM, respectively^[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.

LY2874455 exhibits a rapid, robust, dose-dependent inhibition of tumor growth in all 4 models tested. Importantly, this molecule causes a significant regression of tumor growth in the RT-112, SNU-16, and OPM-2 tumor models, especially when dosed at 3 mg/kg twice a day. Also, LY2874455 exhibits an excellent pharmacokinetic/pharmacodynamic relationship as shown by its dose-dependent inhibition of the tumor growth at TED₅₀ and TED₉₀ (1 and 3 mg/kg, respectively). When tested in the RT-112 tumor xenograft model on an intermittent dosing schedule (twice a day 1 week on and 1 week off or twice a day 2 days on and 2 days off), LY2874455 is also efficacious. When rats are dosed with LY2874455 at 1 and 3 mg/kg, which is 2.6- and 7.7-fold over the TED₅₀ (0.39 mg/kg) obtained in the rat heart IVTI assay, respectively, there are no significant changes observed in blood pressure. However, when rats are dosed with LY2874455 at 10 mg/kg, which is 25.6-fold over the TED₅₀, there are significant increases observed in arterial pressures^[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.

444.31

C₂₁H₁₉Cl₂N₅O₂

1254473-64-7

Room temperature in continental US; may vary elsewhere.

DMSO : 50 mg/mL (112.53 mM; Need ultrasonic)

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    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 2.5 mg/mL (5.63 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (5.63 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-CD in saline)

  Solubility: 2.5 mg/mL (5.63 mM); Suspended solution; Need ultrasonic

  此方案可获得 2.5 mg/mL (5.63 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 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
• 3.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 2.5 mg/mL (5.63 mM); Suspended solution

  此方案可获得 ≥ 2.5 mg/mL (5.63 mM，饱和度未知) 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 μL玉米油中，混合均匀。

• [1]. Zhao G, et al. A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models. Molecular Cancer Therapeutics (2011), 10(11), 2200-2210.

Reaction mixtures contained 8 mM Tris-HCl (pH 7.5), 10 mM HEPES, 5 mM dithiothreitol, 10 μM ATP, 0.5 μCi ³³P-ATP, 10 mM MnCl₂, 150 mM NaCl, 0.01% Triton X-100, 4% DMSO, 0.05 mg/mL poly(Glu:Tyr) (4:1, average molecular weight of 20-50 kDa), and 7.5, 7.5, and 16 ng of FGFR1, FGFR3, and FGFR4, respectively, and are incubated at room temperature for 30 minutes followed by termination with 10% H₃PO₄. The reaction mixtures are transferred to 96-well MAFB filter plates that are washed 3 times with 0.5% H₃PO₄. After air-drying, the plates are read with a Trilux reader^[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.

The different multiple myeloma cancer cell lines KMS-11 and OPM-2 cells, L-363, and U266 cells are used. Cells (2,000 per well) are first grown in RPMI for 6 hours and treated with LY2874455 at 37°C for 3 days. The cells are stained at 37°C for 4 hours and then solubilized at 37°C for 1 hour. Finally, the plate is read at 570 nm using a plate reader^[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]
RT-112, OPM-2 (DSMZ), SNU-16, and NCI-H460 cells (RT-112: 2×10⁶ per animal; OPM-2: 10⁷ per animal; SNU-16: 10⁶ per animal; and NCI-H460: 3×10⁶ per animal) are mixed with Matrigel (1:1) and implanted subcutaneously into the rear flank of the mice (female, CD-1 nu/nu for RT-112, OPM-2, and NCI-H460 cells and female, severe combined immunodeficient for SNU-16 cells). The implanted tumor cells grow as solid tumors. To test the efficacy of LY2874455 in these models, the animals are orally dosed with approximately 1 mg/kg (TED₅₀) or 3 mg/kg (TED₉₀) of LY2874455 in 10% Acacia once (every day) or twice a day after tumors reach approximately 150 mm³. The tumor volume and body weight are measured twice a week.
Rats^[1]
Four male rats per group are dosed with vehicle (1% hydroxyethylcellulose, 0.25% polysorbate 80, and 0.05% Dow Corning antifoam 1510-US in purified water) on day 1 and LY2874455 (1, 3, and 10 mg/kg) on day 0. On day 1, at least 120 minutes of control data are collected following vehicle administration. On day 0, data are collected for approximately 20 hours beginning after the last animal is dosed.

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]. Zhao G, et al. A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models. Molecular Cancer Therapeutics (2011), 10(11), 2200-2210.