7KWA

Structure of DCN1 bound to N-((4S,5S)-3-(aminomethyl)-7-ethyl-4-(4-fluorophenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(trifluoromethyl)benzamide

Summary for 7KWA

• Entry DOI: 10.2210/pdb7kwa/pdb
• Descriptor: Endolysin,DCN1-like protein 1, N-[(4S,5S)-3-(aminomethyl)-7-ethyl-4-(4-fluorophenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-(trifluoromethyl)benzamide (3 entities in total)
• Functional Keywords: inhibitor complex, ligase, ligase-inhibitor complex, ligase/inhibitor
• Biological source: Enterobacteria phage RB59; More
• Total number of polymer chains: 1
• Total formula weight: 44858.89

Authors

Kim, H.S.,Hammill, J.T.,Schulman, B.A.,Guy, R.K.,Scott, D.C. (deposition date: 2020-11-30, release date: 2021-07-14, Last modification date: 2023-10-18)

Primary citation

Kim, H.S.,Hammill, J.T.,Scott, D.C.,Chen, Y.,Rice, A.L.,Pistel, W.,Singh, B.,Schulman, B.A.,Guy, R.K.
Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M.
J.Med.Chem., 64:5850-5862, 2021

PubMed 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, , 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 IC for 24 h in mice.

PubMed: 33945681
DOI: 10.1021/acs.jmedchem.1c00035

Experimental method

X-RAY DIFFRACTION (1.572 Å)