Discovery of AB801, a Potent and Selective Inhibitor of AXL Receptor Tyrosine Kinase for Use in Cancer Therapy

AXL receptor tyrosine kinase (AXL), a transmembrane protein highly expressed in a variety of cancers, has been implicated in the development of resistance to various forms of therapy and poor patient outcomes. Although several strategies have been postulated to limit AXL signaling and thus tumor growth, further refinement is possible. In this Drug Annotation, we report the structure-based design, SAR-driven optimization, preclinical pharmacokinetics (PK), and synthetic chemistry which enabled the discovery of AB801. AB801 is a novel, highly potent, selective, and orally bioavailable AXL inhibitor. In addition to its characterization in a variety of in vitro assays and in vivo studies, AB801 was recently dosed in healthy volunteers and is currently being evaluated clinically as a single agent in advanced solid tumors and in combination with chemotherapy for the treatment of nonsmall cell lung cancer (NSCLC).