Abstract
TYRO3 plays a critical role in platelet aggregation as a platelet response amplifier. Selective inhibition of TYRO3 may provide therapeutic benefits for treating thrombosis and related diseases without increasing bleeding risk. We employed a structure-based approach and discovered a novel and potent TYRO3 inhibitor UNC9426 (12) with an excellent Ambit selectivity score (S50 (1.0 μM) = 0.026) and favorable pharmacokinetic properties in mice. Treatment with UNC9426 reduced platelet aggregation without increasing bleeding time and blocked TYRO3-dependent functions in tumor cells and macrophages, implicating its utility for multiple indications.