Discovery of A‑910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor

TAM receptor tyrosine kinases have emerged as promising
therapeutic
targets for cancer treatment due to their roles in both tumor intrinsic
survival mechanisms and suppression of antitumor immunity within the
tumor microenvironment. Inhibiting MerTK and Axl selectively is believed
to hinder cancer cell survival, reverse the protumor myeloid phenotype,
and suppress efferocytosis, thereby eliciting an antitumor immune
response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved
through a structure-based medicinal chemistry campaign. The lead compound
exhibits favorable oral bioavailability, exceptional kinome selectivity,
and significantly improved in vivo target engagement. These findings
support the use of A-910 as an orally bioavailable in
vivo tool compound for investigating the immunotherapy potential of
dual MerTK/Axl inhibition.