c-Met inhibitors with different binding modes - Two is better than one

Primary and acquired resistance to kinase inhibitors due to preexisting mutations of the target or to mutations that arise as a result of selection by therapy is now a common theme in cancer patients treated with these drugs. Different classes of inhibitors for the same target have been successful in overcoming, at least temporarily, these resistance mechanisms because of their ability to interact with the mutated receptor. Therefore, having different classes of inhibitors for a given target might offer more treatment options for cancer patients. c-Met inhibitors are emerging as potentially important new cancer drugs and profiling these agents against several mutant receptors has begun. We have recently identified c-Met inhibitors that are active against wild-type and mutated c-Met variants. X-ray crystallography revealed that this class of inhibitors binds c-Met very differently than another c-Met inhibitor that shows primary resistance to some c-Met mutants. Our results suggested that it is possible to identify c-Met inhibitors that will be active against a range of c-Met mutations.