Design, Synthesis, and Characterization of 4‑Aminoquinazolines as Potent Inhibitors of the G Protein-Coupled Receptor Kinase 6 (GRK6) for the Treatment of Multiple Myeloma

Both previous and additional genetic
knockdown studies reported
herein implicate G protein-coupled receptor kinase 6 (GRK6) as a critical
kinase required for the survival of multiple myeloma (MM) cells. Therefore,
we sought to develop a small molecule GRK6 inhibitor as an MM therapeutic.
From a focused library of known kinase inhibitors, we identified two
hits with moderate biochemical potencies against GRK6. From these
hits, we developed potent (IC50 < 10 nM) analogues with
selectivity against off-target kinases. Further optimization led to
the discovery of an analogue (18) with an IC50 value of 6 nM against GRK6 and selectivity against a panel of 85
kinases. Compound 18 has potent cellular target engagement
and antiproliferative activity against MM cells and is synergistic
with bortezomib. In summary, we demonstrate that targeting GRK6 with
small molecule inhibitors represents a promising approach for MM and
identify 18 as a novel, potent, and selective GRK6 inhibitor.