GNF-7
中文名称:
GNF-7
中文同义词:
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;BCR-ABL WT和BCR-ABL T315I抑制剂(GNF-7);化合物GNF7
英文名称:
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)-
英文同义词:
BenzaMide, N-[3-[1,4-dihy...;GNF-7;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;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;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)-;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;GNF-7, >98%;CS-1945
CAS号:
839706-07-9
分子式:
C28H24F3N7O2
分子量:
547.53
EINECS号:
相关类别:
小分子抑制剂;生化试剂;抑制剂;细胞生物学试剂
Mol文件:
839706-07-9.mol
密度
1.404±0.06 g/cm3(Predicted)
酸度系数(pKa)
12.82±0.70(Predicted)
生物活性
GNF-7 是一种多重激酶抑制剂。GNF-7 是 Bcr-Abl 的抑制剂，对 Bcr-AblWT 和 Bcr-AblT315I 作用的 IC50 值分别为 133 nM 和 61 nM。GNF-7 对 ACK1 和 GCK 也具有抑制活性，IC50 分别为 25 nM 和 8 nM。GNF-7 可用于血液恶性肿瘤的研究。
靶点
IC50: 133 nM (Bcr-Abl WT ), 61 nM (Bcr-Abl T315I ), 25 nM (ACK1), 8 nM (GCK)
体外研究
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.
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.
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 Line:
OCI-AML3 cells
Concentration:
1 μM
Incubation Time:
24 hours
Result:
Induced of G0-G1 arrest.
体内研究
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).
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).
