839706-07-9 GNF-7

• 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).

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