GNF 5

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Background

GNF-5 is an analogue of GNF-2 and a selective non-ATP competitive inhibitor of Bcr-Abl with an IC50 value of 0.1 to >10 µM in various cancer cell lines. Bcr-Abl is a fusion gene that results from the head-to-tail fusion of the Bcr and Abl genes[1]. Bcr-Abl upregulates production of tyrosine kinase and plays a central role in the pathogenesis of chronic myelogenous leukemia (CML) [1]. GNF-5 has the same chemical structure as its parent molecule (GNF-2) with the exception of N-hydroxyethyl carboxamide at its 4-position and such modification provided GNF-5 a longer half-life from (2.30 hrs)[2]. Similar with GNF-2, GNF-5 allosterically inhibits the proliferation of Bcr-Abl positive cell by binding to the myristate-binding site of Abl and induces cell apoptosis[3]. In steady-state kinetic analyses, GNF-5 was able to inhibit wild type Abl with an IC50 value of 0.22 µM[2]. In addition, GNF-5 also has a similar effectiveness against various imatinib® resistance cell lines: In E255V and T315I mutant Ba/F3 cells, a 12-day incubation of GNF-5 2 was able to inhibit the proliferation of cells with a IC50 value of 0.38 and 5 µM, respectively[2]. In mice injected with wild-type Bcr-Abl and luciferase expressing Ba/F3 cells, continuous injection of GNF-5 for 7 days (50 mg/kg, twice per day) normalized peripheral blood cell counts, as well as spleen size[2]. When treating mice that injected with imatinib® resistance T315I Bcr–Abl-transduced bone marrow, daily injection of GNF-5 (75 mg/ kg, twice per day) significantly extended the survival day of mice from 24 days to 22 days[2].

[1]. Rumpold, H. & Webersinke, G. 2011. Molecular pathogenesis of Philadelphia-positive chronic myeloid leukemia - is it all BCR-ABL? Curr Cancer Drug Targets, 11, 3-19.
[2]. Zhang, J., Adrian, F. J., Jahnke, W., et al. 2010. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature, 463, 501-506.
[3]. Karunakaran, U., Park, S. J., Jun, D. Y., et al. Non-receptor tyrosine kinase inhibitors enhances β-cell survival by suppressing the PKCδ signal transduction pathway in streptozotocin – induced β-cell apoptosis. Cellular Signalling.