6P5V

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

Summary for 6P5V

• Entry DOI: 10.2210/pdb6p5v/pdb
• Descriptor: Lysozyme,DCN1-like protein 1 fusion, (4S)-2-METHYL-2,4-PENTANEDIOL, N-[(4S,5S)-1-[(1S)-cyclohex-3-en-1-yl]-7-ethyl-4-(4-fluorophenyl)-3-methyl-6-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methylbenzamide, ... (4 entities in total)
• Functional Keywords: e3 ligase, ligase
• Biological source: Enterobacteria phage T4; More
• Total number of polymer chains: 1
• Total formula weight: 44912.11

Authors

Guy, R.K.,Kim, H.S.,Hammill, J.T.,Scott, D.C.,Schulman, B.A. (deposition date: 2019-05-31, release date: 2019-09-11, Last modification date: 2023-10-11)

Primary citation

Kim, H.S.,Hammill, J.T.,Scott, D.C.,Chen, Y.,Min, J.,Rector, J.,Singh, B.,Schulman, B.A.,Guy, R.K.
Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation.
J.Med.Chem., 62:8429-8442, 2019

PubMed Abstract: Chemical control of cullin neddylation is attracting increased attention based largely on the successes of the NEDD8-activating enzyme (E1) inhibitor pevonedistat. Recently reported chemical probes enable selective and time-dependent inhibition of downstream members of the neddylation trienzymatic cascade including the co-E3, DCN1. In this work, we report the optimization of a novel class of small molecule inhibitors of the DCN1-UBE2M interaction. Rational X-ray co-structure enabled optimization afforded a 25-fold improvement in potency relative to the initial screening hit. The potency gains are largely attributed to additional hydrophobic interactions mimicking the N-terminal acetyl group that drives binding of UBE2M to DCN1. The compounds inhibit the protein-protein interaction, block NEDD8 transfer in biochemical assays, engage DCN1 in cells, and selectively reduce the steady-state neddylation of Cul1 and Cul3 in two squamous carcinoma cell lines harboring DCN1 amplification.

PubMed: 31465221
DOI: 10.1021/acs.jmedchem.9b00410

Experimental method

X-RAY DIFFRACTION (1.398 Å)