| Abstract: |
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. © 2021 American Chemical Society. All rights reserved. |
| Keywords: |
pyridines; cell proliferation; mouse; animal; metabolism; animals; mice; molecular dynamics; drug effect; cell line, tumor; drug design; structure activity relation; structure-activity relationship; chemistry; pyrazole derivative; pyrazoles; signal peptide; intracellular signaling peptides and proteins; tumor cell line; binding site; crystallography, x-ray; binding sites; x ray crystallography; half life time; administration, oral; ubiquitin-conjugating enzymes; drug stability; half-life; pyridine derivative; oral drug administration; ubiquitin conjugating enzyme; molecular dynamics simulation; dcun1d1 protein, human; humans; human; pyrazolopyridine; ube2m protein, human
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