Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

J Med Chem. 2018 Apr 12;61(7):2694-2706. doi: 10.1021/acs.jmedchem.7b01282. Epub 2018 Mar 26.

Abstract

We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1-UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CLint = 170 mL/min/kg). This work lays out the discovery of an orally bioavailable analogue, NAcM-OPT (67). Compound 67 retains the favorable biochemical and cellular activity of compound 7 but is significantly more stable both in vitro and in vivo. Compound 67 is orally bioavailable, well tolerated in mice, and currently used to study the effects of acute pharmacologic inhibition of the DCN1-UBE2M interaction on the NEDD8/CUL pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Biological Availability
  • Carcinoma, Squamous Cell / drug therapy
  • Cell Line, Tumor
  • Cullin Proteins / drug effects*
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lung Neoplasms / drug therapy
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • NEDD8 Protein / antagonists & inhibitors
  • NEDD8 Protein / drug effects
  • Proteins
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Structure-Activity Relationship
  • Ubiquitin-Conjugating Enzymes / antagonists & inhibitors
  • Urea / analogs & derivatives
  • Urea / chemistry

Substances

  • Antineoplastic Agents
  • Cullin Proteins
  • DCUN1D1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • NEDD8 Protein
  • NEDD8 protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • Urea
  • Ubiquitin-Conjugating Enzymes
  • UBE2M protein, human