AXL is a transmembrane protein that is overexpressed in numerous cancers and has been implicated as a driver of resistance to chemo- and immunotherapies. High AXL expression in tumors is generally correlated with tumor growth and poor prognosis in cancer patients, making it an attractive target for cancer therapeutics. AXL can be activated extracellularly by its ligand, growth arrest specific protein 6 (GAS6), or through a ligand-independent pathway triggering receptor dimerization and auto-phosphorylation. This phosphorylation initiates signaling cascades responsible for promoting cancer cell proliferation and survival and an immunosuppressive microenvironment. We have developed a novel series of azaindazole-based AXL inhibitors. Within this series, we have discovered and characterized a compound demonstrating significant anti-tumor efficacy in murine models in combination with other tyrosine kinase inhibitors (TKIs). This compound exhibits good potency in both biochemical (IC<sub>50</sub> = 2.8 nM, 700 μM ATP) and cell-based (IC<sub>50</sub> = 719 nM, 100% serum) assays as well as good selectivity against closely related kinases MERTK and TYRO3. Overall, these efforts have revealed a novel and potent class of small-molecule AXL inhibitors suitable for further preclinical development.

Discovery and characterization of potent and selective AXL receptor tyrosine kinase inhibitors

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