Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration

The pyrimidine core
has been utilized extensively to construct
kinase inhibitors, including eight FDA-approved drugs. Because the
pyrimidine hinge-binding motif is accommodated by many human kinases,
kinome-wide selectivity of resultant molecules can be poor. This liability
was seen as an advantage since it is well tolerated by many understudied
kinases. We hypothesized that nonexemplified aminopyrimidines bearing
side chains from well-annotated pyrimidine-based inhibitors with off-target
activity on understudied kinases would provide us with useful inhibitors
of these lesser studied kinases. Our strategy paired mixing and matching
the side chains from the 2- and 4-positions of the parent compounds
with modifications at the 5-position of the pyrimidine core, which
is situated near the gatekeeper residue of the binding pocket. Utilizing
this approach, we imparted improved kinome-wide selectivity to most
members of the resultant library. Importantly, we also identified
potent biochemical and cell-active lead compounds for understudied
kinases like DRAK1, BMP2K, and MARK3/4.