Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group

Although
all kinases share the same ATP binding pocket, subtle
differences in the residues that form the pocket differentiate individual
kinases’ affinity for ATP competitive inhibitors. We have found
that by introducing a single methyl group, the selectivity of our
MERTK inhibitors over another target, FLT3, was increased up to 1000-fold
(compound 31). Compound 19 was identified
as an in vivo tool compound with subnanomolar activity against MERTK
and 38-fold selectivity over FLT3 in vitro. The potency and selectivity
of 19 for MERTK over FLT3 were confirmed in cell-based
assays using human cancer cell lines. Compound 19 had
favorable pharmacokinetic properties in mice. Phosphorylation of MERTK
was decreased by 75% in bone marrow leukemia cells from mice treated
with 19 compared to vehicle-treated mice.