Background:

UNC2881 is a selective inhibitor of Mer tyrosine kinase [1].

Mer is a member of the TAM (Tyro3, Axl and Mer) receptor tyrosine kinase (RTK) subfamily with growth-arrest-specific-6 (Gas6) as an endogenous ligand. Mer plays an important role in platelet aggregation and macrophage activity.

UNC2881 is a novel and specific Mer tyrosine kinase inhibitor. In kinase inhibition assays, UNC2881 (430 nM) inhibited MER, FGFR1, KDR, EGFR, ITK and TRKA by greater than 50%. In 697 B-ALL cells, UNC2881 inhibited Mer phosphorylation with IC50 value of 22 nM. Also, UNC2881 inhibited ligand-dependent phosphorylation of a chimeric protein consisting of the intracellular domain of Mer and the extracellular domain of the epidermal growth factor receptor (EGFR). In human platelet-rich plasma, UNC2881 inhibited platelet aggregation induced by fibrillar Type I equine collagen by greater than 25%. UNC2881 also inhibited ATP release, a marker of platelet activation [1].

In mice, UNC2881 exhibited 14% oral bioavailability and high systemic clearance. UNC2881 was sufficient for in vitro or short-term in vivo studies [1].

Reference:
[1].  Zhang W, McIver AL, Stashko MA, et al. Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis. J Med Chem, 2013, 56(23): 9693-9700.