- 英文名称
- 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
- 分子式
- C28H24F3N7O2
- 分子量
- 547.53
- 中文别名
- 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; N-(4-甲基-3-(1-甲基-7-((6-甲基吡啶-3-基)氨基)-2-氧代-1,2-二氢嘧啶并[4,5-D]嘧啶-3(4H)-基)苯基)-3-(三氟甲基)苯甲酰胺; GNF-7,RAS信号抑制剂; GNF-7试剂; 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-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; N-(4-Methyl-3-{1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl}phenyl)-3-(trifluoromethyl)benzamide
- 用途
- - 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.
- 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).
