Biological Activity
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].
References
[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.
