Tivantinib is a Selective c-Met Tyrosine Kinase Inhibitor
Posted On 2022-04-30
c-Met (hepatocyte growth factor receptor, HGFR) is a type of receptor tyrosine kinase which belongs to the MET family. c-Met exsists in the surfaces of various epithelial cells. Hepatocyte growth factor (HGF) is the ligand for c-Met. HGF belongs to the soluble cytokine family and is also a member of the plasminogen-related growth factor family. The binding of HGF to c-Met initiates a series of intracellular signals. Under normal conditions, HGF/c-Met can mediate embryogenesis, tissue regeneration, wound healing, and the formation of nerve and muscle. Thus, this axis plays an important role in normal biological functions in humans.
However, as a type of proto-oncogene, abnormal activation of c-Met can promote the development and progression of multiple cancers. The HGF/c-Met axis can stimulate various downstream signaling pathways in tumor cells, such as PI3K/AKT, JAK/STAT, Ras/MAPK, SRC, and Wnt/β-catenin, among others. These aforementioned phenomena regulate tumor proliferation, invasion, metastasis, anti-apoptosis, EMT, and angiogenesis. Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients. Thus, it is extremely important to understand the role of c-Met in cancer.
Tivantinib is a selective and orally active c-MET inhibitor.
Tivantinib, formerly known as ARQ 197, is a selective, orally active, and non-ATP competitive inhibitor of c-MET. Importantly, Tivantinib strongly inhibits c-Met autoactivation by stabilizing the inactive nonphosphorylated configuration of the kinase, leading to the arrest of cell growth. It arrests c-MET-dependent downstream signaling pathways by perturbing constitutive and ligand-mediated MET phosphorylation, resulting in a reduction in proliferation, invasion, metastasis, and the induction of caspase-dependent apoptosis. Other mechanisms of action for tivantinib might be due to it could directly bind microtubules. Thus, it disrupts microtubule function inducing mitotic catastrophe, and leads to subsequent apoptosis. Tivantinib is effective against various cancers, including non-small-cell lung cancer, colon cancer, gastric cancer, and hepatocellular carcinoma.
All in all, Tivantinib is a selective and orally active inhibitor of c-MET. Tivantinib exhibits anti-tumor activity.
Zhang Y, et, al. Mol Cancer. 2018 Feb 19;17(1):45.