In vitro activity: UNC-2025 is a novel, potent and orally bioavailable dual inhibitor of MER/FLT3 with IC50 of 0.74 nM and 0.8 nM, respectively, it displayed about 20-fold selectivity over Axl and Tyro3. UNC-2025 is capable of inhibiting Mer phosphorylation in vivo. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that UNC-2025 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

Kinase Assay: UNC2025 hydrochloride is a potent and orally bioavailable Mer/Flt3 dual inhibitor with IC50 of 0.8/0.74 nM for Mer/Flt3. UNC2025 was capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

Cell Assay: In 697 B-ALL cells, UNC-2025 potently inhibits Mer phosphorylation with IC50 of 2.7 nM. In A549 NSCLC and Molm-14 AML cell lines, UNC-2025 causes significant inhibition of colony formation dependent on Mer8 and Flt3. In H2228 and H1299 cell lines, UNC-2025 inhibits MERTK oncogenic signaling downstream, such as basal and stimulated pAKT and pERK1/2. In four NSCLC cell lines, UNC-2025 also induces apoptotic cell death, and decreases colony formation.