6p5v

Publication Abstract from PubMed

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.

Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation.,Kim HS, Hammill JT, Scott DC, Chen Y, Min J, Rector J, Singh B, Schulman BA, Guy RK J Med Chem. 2019 Sep 26;62(18):8429-8442. doi: 10.1021/acs.jmedchem.9b00410. Epub, 2019 Sep 13. PMID:31465221^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.