GNF-7

生物活性靶点体外研究体内研究 GNF-7 试剂级价格

GNF-7

CAS号:839706-07-9
英文名: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)-
中文名:GNF-7
CBNumber:CB42615277
分子式:C28H24F3N7O2
分子量:547.53
MOL File:839706-07-9.mol

GNF-7化学性质

密度 :1.404±0.06 g/cm3(Predicted)
储存条件 :Store at -20°C
溶解度 :insoluble in EtOH; insoluble in H2O; ≥5.48 mg/mL in DMSO
形态 :solid
酸度系数(pKa) :12.82±0.70(Predicted)
颜色 :White to off-white

GNF-7性质、用途与生产工艺

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).