Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor

The receptor tyrosine kinase Axl
plays important roles in promoting
cancer progression, metastasis, and drug resistance and has been identified
as a promising target for anticancer therapeutics. We used molecular
modeling-assisted structural optimization starting with the low micromolar
potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity
profiling showed that 13c could inhibit the well-known
oncogenic kinase Met with equal potency to its inhibition of Axl superfamily
kinases. Compound 13c significantly inhibited cellular
Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation,
and restrained Gas6/Axl-mediated cancer cell migration or invasion.
Furthermore, 13c exhibited significant antitumor efficacy
in Axl-driven and Met-driven tumor xenograft models, causing tumor
stasis or regression at well-tolerated doses. All these favorable
data make 13c a promising therapeutic candidate for cancer
treatment.