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.

Automated summary

The pyrimidine core has been widely used in constructing kinase inhibitors, and the strategy of utilizing nonexemplified aminopyrimidines with side chains from annotated inhibitors has provided useful inhibitors for understudied kinases. By mixing and matching side chains from parent compounds and modifying the 5-position of the pyrimidine core, improved kinome-wide selectivity was achieved. Important lead compounds for understudied kinases such as DRAK1, BMP2K, and MARK3/4 were also identified through this approach.