Tyro3, Axl, and Mer are members of the TAM family of receptor tyrosine kinases that have signaling roles in normal and malignant cells. UNC2250 is an inhibitor of Mer kinase activity, blocking the steady-state phosphorylation of endogenous Mer in 697 B-ALL cells with an IC50 value of 9.8 nM. It is selective for Mer over a panel of both tyrosine and serine-threonine kinases, including Tyro3 and Axl. UNC2250 also inhibits ligand-dependent phosphorylation of a chimeric EGFR-Mer protein and blocks colony formation in soft agar cultures of BT-12 rhabdoid tumor and Colo699 NSCLC cell lines. UNC2250 displays good pharmacokinetic properties in mice following intravenous or oral administration.
(1r,4r)-4-((2-(Butylamino)-5-(5-(morpholinomethyl)pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexanol inhibits steady-state phosphorylation of endogenous Mer and blocks ligand-stimulated activation of a chimeric EGFR-Mer protein. (1r,4r)-4-((2-(Butylamino)-5-(5-(morpholinomethyl)pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexanol also decreases colony-forming potential in rhabdoid and NSCLC tumor cells.
[1] zhang w, zhang d, stashko m a, et al. pseudo-cyclization through intramolecular hydrogen bond enables discovery of pyridine substituted pyrimidines as new mer kinase inhibitors. journal of medicinal chemistry, 2013, 56(23): 9683-9692.
