生物活性

• 描述Mer is a member of the TAM (Tyro3, Axl and Mer) receptor tyrosine kinase (RTK) subfamily with growth-arrest-specific-6 (Gas6) as one of the endogenous ligands. Elevated Mer activation has been strongly associated with the oncogenesis of a number of human cancers. Recently, Mer has also been shown to play important roles in regulating macrophage activity and platelet aggregation. UNC2881 is a specific Mer tyrosine kinase inhibitor with an IC₅₀ of 4.3 nM, and its selectivity is 83-fold and 58-fold higher than that of Axl and Tyro3, respectively. When applied to live cells, UNC2881 inhibits steady-state Mer kinase phosphorylation with an IC₅₀ value of 22 nM. Treatment with UNC2881 is also sufficient to block EGF (epidermal growth factor)-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, UNC2881 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis. In mice, UNC2881 had high systemic clearance (94.5 mL/min/kg) and 14% oral bioavailability. The terminal half-life was 0.80 h. The volume of distribution was 2-fold greater than the normal volume of total body water (0.70 L/kg).