GNF-5 is a selective non-ATP competitive inhibitor ofBcr-Abl with IC50 of 220 nM, it's an analogue of GNF-2 with improved pharmacokinetic properties.
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Bcr-Abl fusion protein is formed as a result of a chromosomal translocation event forming the Philadelphia chromosome that fuses the breakpoint cluster region (BCR) gene to the N-terminus of the Abelson tyrosine kinase (ABL1) gene, which cause Chronic myelogenous leukemia(CML)[3]. GNF-5 is a highly selective non-ATP competitive inhibitor of Bcr-Abl with IC50 value of 0.22μM. GNF-5 alters conformation and hydrogen exchange in the peptide near the ATP-site. In vitro, GNF-5 exhibited inhibition of wild-type Bcr-Abl transformed Ba/F3 cells. Treatment with 10μM GNF-5 significantly inhibited the proliferation of T315I Bcr-Abl Ba/f3 cells[1]. Treatment MDA-MB-231 cells with 10μM GNF-5 decreased in active, matrix-degrading invadopodia, but did not affect cell proliferation. In addition, GNF-5 affected cortactin tyrosine phosphorylation and reduced actin barbed end generation in MDA-MB-231 cells[4]. In vivo, oral administered GNF-5 at 75mg/kg twice daily significantly extended survival of the mice transplanted with T315I Bcr-Abl transduced bone marrow[1].Treatment MDA-MB-231 cells xenograft mouse model with GNF-5 at dose of 100mg/kg once daily via oral gavage for 4 weeks suppressed matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs[4].
作用机制
GNF-5 binds to the myristate pocket near the C-terminus of the ABL kinase domain and transmits structural changes to the ATP binding site[4].
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