Kim, Ho Shin; Hammill, Jared T.; Scott, Daniel C.; Chen, Yizhe; Rice, Amy L.; Pistel, William; Singh, Bhuvanesh; Schulman, Brenda A.; Guy, R. Kiplin published the artcile< Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M>, Product Details of C4H8O3, the main research area is carcinoma DCN1 UBE2M interaction inhibitors NEDD8 pharmacokinetic oral bioavailability.
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 (I), inhibits the interaction of DCN1 and UBE2M, blocks NEDD8 transfer in biochem. assays, thermally stabilizes cellular DCN1, and inhibits anchorage-independent growth in a DCN1 amplified squamous cell carcinoma cell line. Addnl., we demonstrate that a single oral 50 mg/kg dose sustains plasma exposures above the biochem. IC90 for 24 h in mice.
Journal of Medicinal Chemistry published new progress about Antitumor agents. 623-50-7 belongs to class esters-buliding-blocks, and the molecular formula is C4H8O3, Product Details of C4H8O3.
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