Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation

Ho Shin Kim, Jared T. Hammill, Daniel C. Scott, Yizhe Chen, Jaeki Min, Jonah Rector, Bhuvanesh Singh, Brenda A. Schulman, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)8429-8442
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number18
DOIs
StatePublished - Sep 26 2019

Bibliographical note

Funding Information:
We thank the College of Pharmacy NMR Center (University of Kentucky) for NMR support. We acknowledge the High Throughput Biosciences Center, Medicinal Chemistry Center, Compound Management, and High Throughput Analytical Chemistry Centers in Chemical Biology and Therapeutics; Hartwell Center for use of their personnel and facilities. We thank the staff at the ALS 8.2.1 and Sercat 22-ID beamlines at the Advanced Light Source and Advanced Photon Source. B.A.S. and D.C.S. acknowledge NIH Grants R37GM069530 and P30CA021765. J.T.H. acknowledges NIH Grant F32GM113310; ALSAC/St. Jude.

Publisher Copyright:
© 2019 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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