GZD856 是一种有效的和具有口服活性的PDGFRα/β抑制剂，IC50值分别为 68.6 和 136.6 nM。GZD856 也是Bcr-AblT315I的抑制剂，对天然 Bcr-Abl 和 T315I 突变型的IC50值分别为 19.9 和 15.4 nM。GZD856 具有抗肿瘤活性。
| 生物活性 | GZD856 formic is a potent and orally activePDGFRα/βinhibitor, withIC50s of 68.6 and 136.6 nM, respectively. GZD856 formic is also aBcr-AblT315Iinhibitor, withIC50s of 19.9 and 15.4 nM for nativeBcr-Abland the T315I mutant. GZD856 formic has antitumor activity[1][2]. |
| IC50& Target[1][2] | PDGFRα 68.6 nM (IC50) | PDGFRβ 136.6 nM (IC50) | Bcr-AblT315I 15.4 nM (IC50) | Bcr-Abl 19.9 nM (IC50) |
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体外研究
(In Vitro) | GZD856 (0.0032-10 μM, 72 h) exerts antiproliferative activity against a panel of lung cancer cells[1].
GZD856 (0.3-3 μM; 24-28 h) induces a dose-dependent G0/G1 phase arrest and apoptosis in H1703 but not A549 cells[1].
GZD856 (0.1-10 μM; 6 h) dose-dependently inhibits the PDGFRα/β phosphorylation and downstream signaling in H1703 and A549 cells[1].
GZD856 inhibits the proliferation of K562, K562R (Q252H) and murine Ba/F3 cells ectopically expressing Bcr-AblWTand Bcr-AblT315I, with IC50s of 2.2, 67.0, 0.64 and 10.8 nM, respectively[2].
Cell Viability Assay[1] | Cell Line: | H1703, A549, Calu-6, 95-D, L-78, HCC827, SPCA-1, H1650, H1299, H522, H332 and H820 NSCLC cells | | Concentration: | 0.0032-10 μM | | Incubation Time: | 72 hours | | Result: | Inhibited PDGFRα-overexpressing H1703 cells, with an IC50of 0.25 μM. |
Apoptosis Analysis[1] | Cell Line: | H1703 and A549 NSCLC cells | | Concentration: | 0.3, 1, 3 μM | | Incubation Time: | 24, 48 hours | | Result: | Led to 54.1% apoptosis in H1703 cells at the concentration of 3.0 μM, whereas only 15.5% apoptotic A549 cells were observed under similar conditions.
Decreased the CDK4, cyclin D2, CDK2 and Cyclin E protein levels and activated of PARP and Caspase-3 cleavage in H1703 cells. |
Western Blot Analysis[1] | Cell Line: | H1703 and A549 NSCLC cells | | Concentration: | 0.1-10 μM | | Incubation Time: | 6 hours | | Result: | Inhibited the phosphorylation of PDGFRα and PDGFRβ in a dose-dependent manner.
Observed the activation of downstream AKT, ERK1/2 and STAT3, with no obvious effects on total protein levels. |
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体内研究
(In Vivo) | GZD856 (10-30 mg/kg, p.o. once daily for 16 d) displays good antitumor activity in both H1703 and A549 lung cancer models and is well tolerated. GZD856 inhibits brain and liver metastasis of lung cancer cells in an A549-Luc orthotopic model[1].
GZD856 (10 mg/kg; p.o. once daily for 8 d) potently inhibits tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I[2].
GZD856 (5 mg/kg; a single i.v.) exhibits a long half-life (T1/2=19.97 h), optimal plasma exposure (Cmax=934.38 μg/L) and a AUC0-∞(8165.8 μg/Loh) in rats[1].
GZD856 (25 mg/kg; a single p.o.) exhibits a long half-life (T1/2=22.2 h), optimal plasma exposure (Cmax=899.5 μg/L) and a good oral bioavailability (BA=78%) in rats[1].
| Animal Model: | Male CB17-SCID mice implanted with H1703 and A549 cancer cells[1] | | Dosage: | 10, 30 mg/kg | | Administration: | Oral gavage once daily for 16 days | | Result: | Displayed antitumor effects in H1703-xenograft mice, with tumor growth inhibition (TGI) values of 20.8% and 74.1% at dosages of 10 and 30 mg/kg, respectively.
Displayed antitumor effects in A549-xenograft mice, with a TGI value of 51.1% at 30 mg/kg.
Was well tolerated in all of the tested groups, with no mortality or significant loss of body weight. |
| Animal Model: | Sprague-Dawley (SD) rats (180-220 g)[1] | | Dosage: | 5 mg/kg for i.v.; 25 mg/kg for p.o. (Pharmacokinetic Analysis) | | Administration: | A single intravenous injection and oral administration | | Result: | I.v.: T1/2=19.97 h; Cmax=934.38 μg/L; AUC0-∞=8165.8 μg/Loh.
P.o.: T1/2=22.2 h; Cmax=899.5 μg/L; BA=78%. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
| 溶解性数据 | In Vitro: DMSO : 250 mg/mL(469.43 mM;Need ultrasonic) 配制储备液 | 1 mM | 1.8777 mL | 9.3886 mL | 18.7772 mL | | 5 mM | 0.3755 mL | 1.8777 mL | 3.7554 mL | | 10 mM | 0.1878 mL | 0.9389 mL | 1.8777 mL |
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: ≥ 2.08 mg/mL (3.91 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (3.91 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。 2. 请依序添加每种溶剂： 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.08 mg/mL (3.91 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (3.91 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 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。 *以上所有助溶剂都可在本网站选购。
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