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详细内容
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Tivantinib (ARQ 197) is an oral, non–adenosine triphosphate-competitive, selective, small-molecule met proto-oncogene (c-MET) inhibitor. The calculated inhibitory constant (Ki) for tivantinib to inhibit recombinant human c-MET was approximately 355 nmol/L.
c-MET, a type of receptor tyrosine kinase, is a high-affinity receptor of the hepatocyte growth factor (HGF). Dysregulated HGF/c-MET-signaling pathway frequently occurs in human cancer [1].
Tivantinib had weak inhibitory effects on VEGF receptor-3 (Flt4), p21-activated kinase 3, calmodulin-dependent kinase II delta, and Pim-1 [1]. Tivantinib displayed cytotoxic activity against a wide panel of human tumor cell lines with an EC50 ranging from 300-600 nmol/L [4]. Remarkably, A549, H3122, PC9 (Del E746_A750), PC9 GR4 (Del E746_A750/T790M), HCC827, HCC827 GR6, H1993 and EBC-1 cell lines showed some degree of sensitivity to tivantinib, with IC50s ranging between 0.36 and 0.8 μM [5]. In tumor cell lines, GTL-16, MKN-45, Hs746T, SNU-5, EBC-1, H1993, NCI-H441, A549, HCT-116, U87-MG, A2780, and TOV-112D, tivantinib indiscriminately inhibited cell proliferation independently of c-MET gene amplification and MET protein expression with an EC50 ranging from 60 to 600 nmol/L. Further research showed that tivantinib promotes mitotic arrest, prevents cells from re-entering G1, and drives them to apoptosis, and induces programmed cell death regardless of the presence or absence of a functional MET kinase [4].
Tivantinib has demonstrated antitumor activity in a wide range of human tumor cell lines and in xenograft models of human lung, colon, prostate, pancreas, and breast cancer [1] [2] [3]. Female 4-week-old athymic nude (nu/nu) mice were used as experimental animals. Tivantinib at a dose of 120 mg/kg significantly inhibited tumor burden in the bone of treated animals compared with the controls, starting from 14 to 21 days after cell injection. Increasing doses of tivantinib decreased the number and the extent of osteolytic lesions [6].
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