UNC2025 is a potent, orally bioavailable inhibitor of the tyrosine kinases Mer and Flt3 (IC50s = 0.74 and 0.80 nM, respectively). It less potently inhibits Axl and Tyro3 (IC50s = 14 and 17 nM, respectively) and a panel of related kinases. UNC2025 blocks colony formation of Mer- and Flt3-dependent tumor cell lines and inhibits Mer phosphorylation in bone marrow leukemia cells in vivo. Pharmacokinetic studies suggest that orally administered UNC2025 at 3 mg/kg will suffice to provide 90% inhibition of Mer and Flt3 at 30 min.
UNC 2025 is Mer/FLT3 dual inhibitor. It can be used in biological study. Novel MERTK inhibitor UNC2025 induced polyploidy and promoted death and senescence in human glioblastoma multiforme cells where high levels of GAS6 MERTK ligand expression correlated with decreased overall survival in patients.
in duplicate versus 305 kinases at carna biosciences using a microcapillary electrophoresis assay, unc2025 inhibited mer and flt3 with the greatest potency. in b-all 697 cell lysates using the atp activx probe assay, unc2025 inhhibited the activity of mer with an ic50 of 0.05 nm. in 697 b-all cells, unc2025 potently inhibited mer phosphorylation with an ic50 of 2.7 nm. similarly, in flt3-itd positive molm-14 acute myeloid leukemia cells, treatment with unc2025 decreased phosphorylation of flt3 with an ic50 of 14 nm. in soft agar cultures of the a549 nsclc and molm-14 aml cell lines, incubation withunc2025 significantly inhibited colony formation, which was known to depend on merand flt3,respectively, for optimal expression of oncogenic phenotypes. much higher concentrations of unc2025 were required to effectively inhibit phosphorylation of axl (ic50 = 122 nm) and tyro3 (ic50 = 301 nm)[1].
in mice with human leukemia xenografts, a single dose of unc2025 (3 mg/kg) administered orally was sufficient to decrease merphospho-protein levels in bone marrow leukemia cells by greater than 90% [1].
[1]. zhang w1,deryckere d,hunter d,liu j,stashko ma,minson ka, et,al. unc2025, a potent and orally bioavailablemer/flt3dual inhibitor.j med chem.2014 aug 28;57(16):7031-41. doi: 10.1021/jm500749d. epub 2014 aug 6.
