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

Jared T. Hammill, Daniel C. Scott, Jaeki Min, Michele C. Connelly, Gloria Holbrook, Fangyi Zhu, Amy Matheny, Lei Yang, Bhuvanesh Singh, Brenda A. Schulman, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish
Pages (from-to)2680-2693
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number7
StatePublished - Apr 12 2018

Bibliographical note

Publisher Copyright:
© 2018 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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