Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M

Ho Shin Kim, Jared T. Hammill, Daniel C. Scott, Yizhe Chen, Amy L. Rice, William Pistel, Bhuvanesh Singh, Brenda A. Schulman, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


The cullin-RING ubiquitin ligases (CRLs) are ubiquitin E3 enzymes that play a key role in controlling proteasomal degradation and are activated by neddylation. We previously reported inhibitors that target CRL activation by disrupting the interaction of defective in cullin neddylation 1 (DCN1), a CRL neddylation co-E3, and UBE2M, a neddylation E2. Our first-generation inhibitors possessed poor oral bioavailability and fairly rapid clearance that hindered the study of acute inhibition of DCN-controlled CRL activity in vivo. Herein, we report studies to improve the pharmacokinetic performance of the pyrazolo-pyridone inhibitors. The current best inhibitor, 40, inhibits the interaction of DCN1 and UBE2M, blocks NEDD8 transfer in biochemical assays, thermally stabilizes cellular DCN1, and inhibits anchorage-independent growth in a DCN1 amplified squamous cell carcinoma cell line. Additionally, we demonstrate that a single oral 50 mg/kg dose sustains plasma exposures above the biochemical IC90 for 24 h in mice.

Original languageEnglish
Pages (from-to)5850-5862
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 13 2021

Bibliographical note

Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M'. Together they form a unique fingerprint.

Cite this