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GNF-7

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Chemical Structure| 839706-07-9 同义名 : -
CAS号 : 839706-07-9
货号 : A472268
分子式 : C28H24F3N7O2
纯度 : 99%+
分子量 : 547.531
MDL号 : MFCD18251569
存储条件：

粉末 Keep in dark place,Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 35 mg/mL(63.92 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • Abl

    E255V, IC50:122 nM

    M351T, IC50:133 nM
描述 The BCR-ABL oncogene is generated by the Philadelphia chromosome (Ph) translocation, fusing the BCR gene to the ABL gene. The BCR-ABL fusion protein has elevated ABL tyrosine kinase activity that is critical for transformation of hematopoietic cells[3]. GNF-7 is a multikinase inhibitor. It is a Bcr-Abl inhibitor, with IC50s of 133 nM and 61 nM for Bcr-AblWT and Bcr-AblT315I, respectively. GNF-7 also possesses inhibitory activity against both ACK1 (activated CDC42 kinase 1) and GCK (germinal center kinase) with IC50s of 25 nM and 8 nM, respectively. GNF-7 can be used for the research of hematologic malignancies[4].GNF-7 inhibited necroptosis in both human and mouse cells, while not protecting cells from apoptosis. Drug affinity responsive target stability assay (DARTS) demonstrated that it binds with RIPK1 and RIPK3. GNF-7 inhibited RIPK1 and RIPK3 kinase activities and thus disrupted RIPK1-RIPK3 necrosome complex formation. In vivo, GNF-7 ameliorated both cisplatin- and ischemia/reperfusion-induced AKI. Orally administration of GNF-7 attenuated renal cell necrosis and reduced pro-inflammatory responses in mouse models of AKI[5]. GNF-7 potently inhibits wild-type Bcr-Abl (IC50<5 nM) and Bcr-Abl mutants such as T315I (IC50=11 nM), G250E (IC50<5 nM), E255V (IC50=10 nM), F317L (IC50<5 nM) and M351T (IC50<5 nM) in cellular assays. 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 Cmax (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)[6].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.83mL

0.37mL

0.18mL

9.13mL

1.83mL

0.91mL

18.26mL

3.65mL

1.83mL
参考文献

[1]Nonami A, Sattler M, et al. Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach. Blood. 2015 May 14;125(20):3133-43.

[2]Choi HG, Ren P, et al. A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl. J Med Chem. 2010 Aug 12;53(15):5439-48.

[3]Martin Sattler,et al. Molecular mechanisms of transformation by the BCR-ABL oncogene. Semin Hematol. 2003. 40(2 Suppl 2), 4-10.

[4]Lu X, et al. Hybrid pyrimidine alkynyls inhibit the clinically resistance related Bcr-Abl(T315I) mutant. Bioorg Med Chem Lett. 2015. 25(17), 3458-63.

[5]Xia Qin,et al. The Bcr-Abl inhibitor GNF-7 inhibits necroptosis and ameliorates acute kidney injury by targeting RIPK1 and RIPK3 kinases. Biochem Pharmacol. 2020. 177, 113947.

[6]Choi HG, et al. A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl. J Med Chem. 2010. 53(15), 5439-48.