Discovery and Characterization of Potent, Selective, and Orally Bioavailable 7-Azaindazole AXL Receptor Tyrosine Kinase Inhibitors

High expression of the membrane-bound receptor tyrosine kinase AXL is linked to poor patient outcomes and therapeutic resistance in a variety of cancers. Selective inhibition of AXL is a promising approach to overcome mechanisms of resistance to standard of care therapies, but it is unclear if reported inhibitors have achieved an appropriate therapeutic window to effectively block AXL signaling in tumors. Herein, we report the initial design and structure-activity relationship (SAR)-driven optimization of a novel series of 7-azaindazole AXL inhibitors. These efforts identified a suitable tool compound for <i>in vivo</i> studies that demonstrated a significant reduction in tumor volume in combination with standard-of-care therapies. Further optimization culminated in the discovery of lead compound <b>68</b>, a molecule with favorable potency, kinome selectivity, oral bioavailability, and safety. SAR insights gained from this campaign helped guide subsequent optimization efforts that ultimately led to the identification of clinical development candidate AB801.