Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation

Chemical control of cullin neddylation
is attracting increased
attention based largely on the successes of the NEDD8-activating enzyme
(E1) inhibitor pevonedistat. Recently reported chemical probes enable
selective and time-dependent inhibition of downstream members of the
neddylation trienzymatic cascade including the co-E3, DCN1. In this
work, we report the optimization of a novel class of small molecule
inhibitors of the DCN1-UBE2M interaction. Rational X-ray co-structure
enabled optimization afforded a 25-fold improvement in potency relative
to the initial screening hit. The potency gains are largely attributed
to additional hydrophobic interactions mimicking the N-terminal acetyl
group that drives binding of UBE2M to DCN1. The compounds inhibit
the protein–protein interaction, block NEDD8 transfer in biochemical
assays, engage DCN1 in cells, and selectively reduce the steady-state
neddylation of Cul1 and Cul3 in two squamous carcinoma cell lines
harboring DCN1 amplification.