Structure-Based Design of Novel Class II c-Met Inhibitors: 1. Identification of Pyrazolone-Based Derivatives

Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as <i>MET</i> gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity

Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, <i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)­oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (<b>1</b>), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of <b>1</b>. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound <b>59e</b> (AMG 458) was ultimately advanced into preclinical safety studies