<b>UNC2025</b>, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

We previously reported a potent small molecule Mer tyrosine kinase inhibitor <b>UNC1062</b>. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of <b>UNC1062</b> to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, <b>11</b>, 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 <b>11</b> has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined