GZD856 formic (C007B-357457)

GZD856 formic is a potent and orally active PDGFRα/β inhibitor, with IC 50 s of 68.6 and 136.6 nM, respectively. GZD856 formic is also a Bcr-Abl T315I inhibitor, with IC 50 s of 19.9 and 15.4 nM for native Bcr-Abl and the T315I mutant. GZD856 formic has antitumor activityIn VitroGZD856 (0.0032-10 μM, 72 h) exerts antiproliferative activity against a panel of lung cancer cells. GZD856 (0.3-3 μM; 24-28 h) induces a dose-dependent G0/G1 phase arrest and apoptosis in H1703 but not A549 cells. GZD856 (0.1-10 μM; 6 h) dose-dependently inhibits the PDGFRα/β phosphorylation and downstream signaling in H1703 and A549 cells. GZD856 inhibits the proliferation of K562, K562R (Q252H) and murine Ba/F3 cells ectopically expressing Bcr-Abl WT and Bcr-Abl T315I , with IC 50 s of 2.2, 67.0, 0.64 and 10.8 nM, respectively. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell 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 IC 50 of 0.25 μM. Apoptosis AnalysisCell 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 AnalysisCell 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.In VivoGZD856 (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 . 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-Abl T315I. GZD856 (5 mg/kg; a single i.v.) exhibits a long half-life (T 1/2 =19.97 h), optimal plasma exposure (C max =934.38 μg/L) and a AUC 0-∞ (8165.8 µg/L•h) in rats . GZD856 (25 mg/kg; a single p.o.) exhibits a long half-life (T 1/2 =22.2 h), optimal plasma exposure (C max =899.5 μg/L) and a good oral bioavailability (BA=78%) in rats . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Male CB17-SCID mice implanted with H1703 and A549 cancer cells 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) 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.: T 1/2 =19.97 h; C max =934.38 μg/L; AUC 0-∞ =8165.8 µg/L•h. P.o.: T 1/2 =22.2 h; C max =899.5 μg/L; BA=78%.Form:SolidIC50& Target:PDGFRα|68.6 nM (IC|50|)|PDGFRβ|136.6 nM (IC|50|)|Bcr-Abl|T315I|15.4 nM (IC|50|)|Bcr-Abl|19.9 nM (IC|50|). Specification: 0.98 Molecular Formula: C30H29F3N6O3 Molecular Weight: 578.58