Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

We
previously reported the discovery, validation, and structure–activity
relationships of a series of piperidinyl ureas that potently inhibit
the DCN1–UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1–UBE2M protein–protein
interaction and DCN1-mediated cullin neddylation in biochemical assays
and reduces levels of steady-state cullin neddylation in a squamous
carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly
metabolized in microsomal models (CLint = 170 mL/min/kg).
This work lays out the discovery of an orally bioavailable analogue,
NAcM-OPT (67). Compound 67 retains the favorable
biochemical and cellular activity of compound 7 but is
significantly more stable both in vitro and in vivo. Compound 67 is orally bioavailable, well tolerated in mice, and currently
used to study the effects of acute pharmacologic inhibition of the
DCN1–UBE2M interaction on the NEDD8/CUL pathway.