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 in vivo 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 68, 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.