Flumatinib (HHGV678) (Synonyms: HH-GV-678)

Flumatinib (HHGV678) 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.

HH-GV-678 can predominantly inhibit the autophosphorylation of Bcr-Abl in K562 cell. In higher concentration, Flumatinib (HHGV678) can inhibit the phosphorylation of c-Kit in Mo7e cell and the phosphorylation of PDGFR in Swiss3T3 cell, however, Flumatinib (HHGV678) has no or little effect on other tyrosine kinase including EGFR, KDR, c-Src and HER2 [1]. Flumatinib (HHGV678) effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P) [2].

The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways of Flumatinib (HHGV678) 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 drug Flumatinib (HHGV678) was the main form recovered in human plasma, urine, and feces. The main metabolites of Flumatinib (HHGV678) in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis [3].

[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.