SIMULTANEOUS ALLOSTERIC INHIBITION OF AXL AND MET RECEPTOR TYROSINE KINASES
Receptor tyrosine kinases, AXL and MET, regulate important cellular functions. In healthy cells, AXL is crucial for cell development, cell migration, and the removal of apoptotic material. Yet, AXL is overexpressed in many cancers and can lead to the development of the resistance to cancer drugs. Previous studies have suggested that AXL suppression, in addition to chemotherapy, could prevent drug resistance. The MET kinase plays a vital part in organogenesis and tissue healing. Like AXL, MET is overexpressed in many cancers. MET's abnormal activity spurs cancer growth and angiogenesis, leading to drug resistance and metastasis. Inhibiting AXL and MET may prevent drug resistance, making them promising targets of cancer therapy. Currently known AXL and MET inhibitors bind at the kinases' active sites. These sites are similar among the kinases, so these inhibitors do not target AXL or MET exclusively. However, the allosteric sites of various kinases are vastly different, allowing a kinase-specific binding. In this work, we computationally designed new drug like small molecules that could allosterically bind both AXL and MET. The designed molecules showed comparable or better drug like properties than known AXL and MET active-site inhibitors. The designed molecules had no implied toxicities and their properties indicated good bioavailability and promising overall drug potential. The molecules bonded each kinase allosterically, with binding energies similar to those for the studied inhibitors. When the designed molecules bound allosterically to AXL or MET, the kinase's active site conformation changed and the ATP molecule could not bind to the site. These results indicate that the AXL/MET allosteric inhibition could potentially impede cancer advancement. 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 cancertreatments.