Computational Design of Druglike Allosteric Inhibitors of AXL and MET Receptor Tyrosine Kinases

Abstract

We report on the computational design of drug-like small molecules that could allosterically bind both the AXL and MET kinases. Such binding would inhibit the kinases and potentially promote apoptosis in cancer cells. AXL and MET are receptor tyrosine kinases (RTKs) that play important roles in healthy cells. However, both AXL and MET are overexpressed in many cancers where they have been linked to drug resistance and metastasis. Several inhibitors of AXL and MET are in various stages of clinical trials. However, generally, they bind to the active site of the kinases. The structure of the active site is similar in many kinases, making them difficult to target selectively. Molecules that broadly inhibit several kinases may damage healthy tissue and lead to undesirable side effects in patients. Efforts in drug discovery have been shifting toward inhibiting the allosteric sites of kinases. Allosteric sites differ among kinases, allowing for selective targeting. The small molecules designed here showed comparable or better drug-like properties than the known AXL and MET active-site inhibitors. Also, they had no implied toxic risks, showed good bioavailability, and had promising overall drug potential. The molecules bonded AXL and MET allosterically with high binding affinities. In the process, the kinase's active site conformation changed, preventing the ATP binding. Our findings, together with previous experimental investigations of active-site AXL and MET inhibitors, strongly imply that the molecules designed here may be effective allosteric inhibitors of both kinases and may lead to the development of novel, more effective cancer treatments.