Through close and solid collaboration, scientists from the Anti-tumor Drug Discovery Team at Shanghai Institute of Materia Medica (SIMM) recently identified a series of novel multi-substituted quinoline analogues exerting promising antitumor potency. This work has recently been published in the Journal of Medicinal Chemistry (2011, 54：2127-2142), and attracted immediate attention to researchers in Calbiochem who requested purchasing and commercializing potential of the lead compound. Meanwhile, this work was also highlighted by SciBX (The Science Business eXchang), a translational science weekly from Nature Publishing Group and BioCentury Publications (http://www.nature.com/scibx/journal/v4/n13/pdf/scibx.2011.363.pdf).

　　c-Met is a unique receptor tyrosine kinase (RTK), structurally distinct from other RTK families. It is the cell surface receptor for hepatocyte growth factor (HGF), and is normally expressed by epithelial cells of many organs (liver, pancreas, prostate, kidney, muscle, and bone narrow). Aberrant HGF/c-Met signaling has been identified in a wide range of human malignancies. Of particular, amplification of the MET oncogene is observed in up to 20% of EGFR-mutant NSCLCs after TKI failure. All these evidences emphasize c-Met as an attractive antitumor therapeutic target. The lead compound 21b, discovery by SIMM displayed IC50 value of 0.95 ± 0.13 nM, compatible to or even better than that of the most potent c-Met inhibitors reported in the literature. It showed promising overall PK profile, and has high potency and extraordinary selectivity to c-Met against c-Met family member Ron, and 12 other tyrosine kinases. Constitutive inhibition of c-Met phosphorylation in c-Met dependent cell lines by this compound was observed. At doses of 100 mg/kg, compound 21b showed statistically significant tumor growth inhibition in both NIH-3T3-TPR-Met and U-87 MG human gliobastoma xenograft models. These results clearly indicated that compound 21b is a potent and highly selective c-Met inhibitor. Such favorable in vitro and in vivo profiles warrant this compound of great value for further investigation either as a chemical tool to probe c-Met-mediated signaling pathway, or as a promising lead compound for further drug design and development.