UNC9435 is a potent, dual TYRO3/MERTK inhibitor with IC50 of 3.7/1.1 nM respectively, has 46-fold and 120-fold selectivity of MERTK over AXL and FLT3, respectively.
UNC9435 also shows selectively against a panel of 30 other kinases.
UNC9435 binds very tightly to TYRO3 and MERTK with <0.51 nM EC50 values for both in NanoBRET assays using HEK293 cells, >3000-fold selective over AXL.
UNC9435 dose-dependently inhibits MERTK and TYRO3 autophosphorylation in NSCLC cells at concentrations as low as 200–250 nM, and reduces AKT signaling downstream of PROS1 stimulation in T11 murine breast cancer cells.
UNC9435 inhibits colony formation in NSCLC cell cultures with EC50 values of 390 nM (H1650) and 900 nM (H1975). UNC9435 also inhibits efferocytosis- i.e. the physiologic clearance of apoptotic material by macrophages mediated by TAM kinases, reduced macrophage uptake of phosphatidylserine-coated microparticles, which mimic apoptotic cells.