Discovery of Novel TYRO3/MERTK Dual Inhibitors

The TAM (TYRO3, AXL, MERTK) family of receptor tyrosine
kinases
has roles in oncogenesis and innate immunity, but the relative importance
of the family members can differ in different contexts and between
tumor types or individual tumors. Dual TYRO3 and MERTK inhibition
may be advantageous for treatment of diseases or in tumors that are
dependent on their coordinated action. Here, we report the discovery
of the first potent dual TYRO3/MERTK inhibitor, UNC9435 (44). UNC9435 has 46-fold and 120-fold selectivity of MERTK over AXL
and FLT3, respectively, and selectively against a panel of 30 other
kinases. TYRO3 and MERTK inhibitory activities were confirmed by NanoBRET
assays in HEK293 cells, with <0.51 nM EC50 values for
both enzymes and >3000-fold selectivity over AXL. UNC9435 also
inhibited
TYRO3, MERTK, and downstream oncogenic signaling in cancer cells and
reduced colony formation in non-small cell lung cancer cultures, indicating
its potential as a novel cancer therapeutic.