| 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 | -20°C, sealed storage, away from moisture *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) |
| 溶解性数据 | In Vitro: DMSO : 100 mg/mL(172.84 mM;Need ultrasonic) 配制储备液 | 1 mM | 1.7284 mL | 8.6418 mL | 17.2837 mL | | 5 mM | 0.3457 mL | 1.7284 mL | 3.4567 mL | | 10 mM | 0.1728 mL | 0.8642 mL | 1.7284 mL |
*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 (sealed storage, away from moisture)。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 |
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