Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

We
previously discovered and validated a class of piperidinyl ureas
that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation
of cullins. Here, we report preliminary structure–activity
relationship studies aimed at advancing our high-throughput screen
hit into a tractable tool compound for dissecting the effects of acute
DCN1–UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled
optimization led to a 100-fold increase in biochemical potency and
modestly increased solubility and permeability as compared to our
initial hit. The optimized compounds inhibit the DCN1–UBE2M
protein–protein interaction in our TR-FRET binding assay and
inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay.
The optimized compounds bind to DCN1 and selectively reduce steady-state
levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell
line. Ultimately, we anticipate that these studies will identify early
lead compounds for clinical development for the treatment of lung
squamous cell carcinomas and other cancers.