Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε

Vaccinia-related kinase 1 (VRK1) and the δ and
ε isoforms
of casein kinase 1 (CK1) are linked to various disease-relevant pathways.
However, the lack of tool compounds for these kinases has significantly
hampered our understanding of their cellular functions and therapeutic
potential. Here, we describe the structure-based development of potent
inhibitors of VRK1, a kinase highly expressed in various tumor types
and crucial for cell proliferation and genome integrity. Kinome-wide
profiling revealed that our compounds also inhibit CK1δ and
CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion.
Complementary studies with existing CK1δ and CK1ε inhibitors
suggest that these kinases may play overlapping roles in cell proliferation
and genome instability. Together, our findings highlight the potential
of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing
the efficacy of existing cancer therapies that target DNA stability
or cell division.