Flumatinib mesylate

Flumatinib mesylate (HH-GV-678 mesylate), a derivative of imatinib, is a multi-kinase inhibitor with IC50 Values of 1.2 nM, 307.6 nM and 2662 nM for c-Abl, PDGFRβ and c-Kit respectively. IC50 Value: 1.2 nM (c-Abl); 307.6 nM(PDGFRβ); 2662 nM (c-Kit) [1] Target: c-Abl; c-Kit; PDGRFβ in vitro: HH-GV-678 can predominantly inhibit the autophosphorylation of Bcr-Abl in K562 cell. In higher concentration, HH-GV-678 can inhibit the phosphorylation of c-Kit in Mo7e cell and the phosphorylation of PDGFR in Swiss3T3 cell, however, HH-GV-678 has no or little effect on other tyrosine kinase including EGFR、KDR、c-Src andHER2 [1]. Flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P) [2]. in vivo: The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways offlumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drugflumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis [3].

References:
[1]. Luo H, et al. HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance. Leukemia. 2010 Oct;24(10):1807-9. [2]. Zhao J, et al. Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants. Cancer Sci. 2013 Nov 10. [3]. Gong A, et al. Metabolism of flumatinib, a novel antineoplastic tyrosine kinase inhibitor, in chronic myelogenous leukemia patients. Drug Metab Dispos. 2010 Aug;38(8):1328-40.

[Effect of flumatinib mesylate on C-MYC, HIF-1alpha and VEGF in U226 line].[Pubmed:24370036]

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013 Dec;21(6):1496-500.

The objective of this study was to investigate the effect of the new generation of tyrosine kinase inhibitor Flumatinib mesylate on C-MYC, HIF-1alpha and VEGF in multiple myeloma (MM) cell line U266. Different concentrations (1, 5, 10 micromol/L) of Flumatinib mesylate were used to act on U266 cell line for 8, 16 and 24 h, and the expression of C-MYC, and HIF-1alpha genes was detected by real-time fluorescence-quantitative PCR, the expression of C-MYC, HIF-1alpha and VEGF was measured by Western blot. The results showed that the gene expression of C-MYC and HIF-1 genes decreased gradually with the increasing of Flumatinib mesylate concentration (P < 0.05). At the same concentration of Flumatinib mesylate, the expression of C-MYC and HIF-1alpha gene decreased gradually with prolonging of treatment time with the Flumatinib mesylate (P < 0.05). When the Flumatinib mesylate acted the U266 cell line for 16 h, the expression of C-MYC, HIF-1alpha and VEGF decreased gradually with the increasing of Flumatinib mesylate concentration (P < 0.05). It is concluded that the Flumatinib mesylate can reduce the expression of C-MYC, HIF-1 alpha and VEGF in U266 cell line in a time- and dose-dependent manners, so Flumatinib mesylate may become a new drug for MM therapy.

Flumatinib mesylate (HH-GV-678 mesylate), a derivative of imatinib, is a multi-kinase inhibitor with IC50 Values of 1.2 nM, 307.6 nM and 2662 nM for c-Abl, PDGFRβ and c-Kit respectively.

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