Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M.
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.
Mesh Terms:
Administration, Oral, Animals, Binding Sites, Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Drug Design, Drug Stability, Half-Life, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Dynamics Simulation, Pyrazoles, Pyridines, Structure-Activity Relationship, Ubiquitin-Conjugating Enzymes
Administration, Oral, Animals, Binding Sites, Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Drug Design, Drug Stability, Half-Life, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Dynamics Simulation, Pyrazoles, Pyridines, Structure-Activity Relationship, Ubiquitin-Conjugating Enzymes
J Med Chem
Date: Dec. 13, 2020
PubMed ID: 33945681
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