Research Progress of Type I Small Molecular Inhibitors for Targeting c-Met
HUANG Mukun1, NAN Xiang2,3, WANG Qiuxu2*, REN Jie3
c-Met (cellular-mesenchymal epithelial transition factor) is a prototype member of a subfamily of heterodimeric RTKs (receptor tyrosine kinases) and is the only known receptor for HGF (hepatocyte growth factor) till now. Under normal physiological conditions, the c-Met/HGF signaling pathway is crucial in mediating various cellular processes including proliferation, motility, migration and invasion, etc. However, aberrant activation of this signalling pathway has frequently been found as the driving factor in human cancers. Moreover, dysregulation of c-Met/HGF signalling has also demonstrated which is associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies. Consequently, c-Met has emerged as a promising target for cancer drug development. Up to now, many strategies have been applied to modulate c-Met/HGF signaling pathway in human clinical studies for the treatment of cancer, and small molecule c-Met inhibitors have draw the most attention from the pharmaceutical industry due to a considerable number of compounds entering clinical trials or being marketed as anticancer drugs. Because type I c-Met inhibitors commonly bind to the entrance of ATP-binding site in “U” shape, this binding mode makes type I c-Met inhibitors more selective than that of type II inhibitors. This review provides an overview of c-Met/HGF signaling pathway in cancer and reviews the recent advancements in medicinal chemistry development and clinical applications of type I small molecule c-Met inhibitors.
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