AMG-208 and Prostatic-Neoplasms

The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.

Topics: Animals; Cell Proliferation; Drug Design; Drug Discovery; Hepatocyte Growth Factor; Humans; Male; Mice; Microsomes, Liver; Models, Molecular; Molecular Structure; Phosphorylation; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Quinolines; Rats; Rats, Sprague-Dawley; Signal Transduction; Tissue Distribution; Triazoles; Xenograft Model Antitumor Assays