Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 9, Pages 5850-5862Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00035
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Funding
- NIH [R01CA247365, R37GM069530, P30CA021765, F32GM113310]
- ALSAC/St. Jude
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This study has improved the pharmacokinetic performance of inhibitors targeting cullin-RING ubiquitin ligases and established the impact of the inhibitor on tumor cell growth.
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.
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