839706-07-9
基本信息
BCR-ABL WT和BCR-ABL T315I抑制剂(GNF-7)
N-[3-[1,4-二氢-1-甲基-7-[(6-甲基-3-吡啶基)氨基]-2-氧代嘧啶并[4,5-D]嘧啶-3(2H)-基]-4-甲基苯基]-3-(三氟甲基)苯甲酰胺
CS-1945
GNF-7, >98%
BenzaMide, N-[3-[1,4-dihy...
N-[4-methyl-3-[1-methyl-7-[(6-methylpyridin-3-yl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide
N-[3-[1,4-Dihydro-1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxopyrimido[4,5-d]pyrimidin-3(2H)-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide
N-(4-Methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide
BenzaMide, N-[3-[1,4-dihydro-1-Methyl-7-[(6-Methyl-3-pyridinyl)aMino]-2-oxopyriMido[4,5-d]pyriMidin-3(2H)-yl]-4-Methylphenyl]-3-(trifluoroMethyl)-
物理化学性质
| 密度 | 1.404±0.06 g/cm3(Predicted) |
| 储存条件 | -20°C储存 |
| 溶解度 | insoluble in EtOH; insoluble in H2O; ≥5.48 mg/mL in DMSO |
| 酸度系数(pKa) | 12.82±0.70(Predicted) |
| 形态 | 固体 |
| 颜色 | White to off-white |
常见问题列表
IC50: 133 nM (Bcr-Abl WT ), 61 nM (Bcr-Abl T315I ), 25 nM (ACK1), 8 nM (GCK)
GNF-7 potently inhibits wild-type Bcr-Abl (IC
50
<5 nM) and Bcr-Abl mutants such as T315I (IC
50
=11 nM), G250E (IC
50
<5 nM), E255V (IC
50
=10 nM), F317L (IC
50
<5 nM) and M351T (IC
50
<5 nM) in cellular assays.
GNF-7 (1 μM; 2 hours) suppresses AKT/mTOR signaling and GCK downstream.
GNF-7 (1 μM; 24 hours) induces of apoptosis and cell cycle arrest in NRAS mutant cell lines.
Western Blot Analysis
| Cell Line: | Ba/F3-NRAS-G12D cells, OCI-AML3 cells |
| Concentration: | 1 μM |
| Incubation Time: | 2 hours |
| Result: | Caused a decreased level of phosphorylation of p70S6K1, AKT (S473), JNK, and p38. |
Apoptosis Analysis
| Cell Line: | OCI-AML3 cells |
| Concentration: | 1 μM |
| Incubation Time: | 24 hours |
| Result: | Increased the levels of both cleaved PARP and cleaved caspase 3 and diminished bcl-2 and MCL1. |
Cell Cycle Analysis
| Cell Line: | OCI-AML3 cells |
| Concentration: | 1 μM |
| Incubation Time: | 24 hours |
| Result: | Induced of G0-G1 arrest. |
GNF-7 (10-20 mg/kg; o.p.; daily; for 7 days) displays significant in vivo efficacy against T315I Bcr-Abl in the bioluminescent xenograft mouse model.
GNF-7 exhibits moderate oral bioavailability (mice 36%) and C
max
(mice 3616 nM) following oral administration (mice 20 mg/kg).
GNF-7 exhibits terminal elimination half-lives (mice 3.8 h) due to high plasma clearance (8.6 mL/min/kg) following intravenous injection (mice 5 mg/kg).
| Animal Model: | 6-8 weeks old SCID beige female mice, with Ba/F3-T315I-Bcr-Abl cells xenograft |
| Dosage: | 10 mg/kg, 20 mg/kg |
| Administration: | Oral administration, daily, for 7 days |
| Result: | Effectively inhibited tumor growth of T315I-Bcr-Abl-Ba/F3 cells in mice at low doses (10 mg/kg). |
| Animal Model: | 5-6 weeks old male Balb/c mice (20-25 g) |
| Dosage: | 5 mg/kg for i.v.; 20 mg/kg for i.g. (Pharmacokinetic Analysis) |
| Administration: | Intravenous injection and oral gavage |
| Result: | Oral bioavailability (36%), C max (3616 nM), T 1/2 (3.2 h). |