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 EC(50) 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.