6BG3

Structure of (3S,4S)-1-benzyl-4-(3-(3-(trifluoromethyl)phenyl)ureido)piperidin-3-yl acetate bound to DCN1

6BG3 の概要

• エントリーDOI: 10.2210/pdb6bg3/pdb
• 分子名称: Endolysin, DCN1-like protein 1 chimera, N-{(3S,4S)-1-benzyl-3-[(1S)-1-hydroxyethoxy]piperidin-4-yl}-N'-[3-(trifluoromethyl)phenyl]urea (3 entities in total)
• 機能のキーワード: e3 ligase, hydrolase, ligase-inhibitor complex, ligase/inhibitor
• 由来する生物種: Enterobacteria phage T4; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44744.81

構造登録者

Guy, R.K.,Schulman, B.A.,Scott, D.C.,Hammill, J.T. (登録日: 2017-10-27, 公開日: 2018-09-26, 最終更新日: 2023-10-04)

主引用文献

Hammill, J.T.,Scott, D.C.,Min, J.,Connelly, M.C.,Holbrook, G.,Zhu, F.,Matheny, A.,Yang, L.,Singh, B.,Schulman, B.A.,Guy, R.K.
Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation.
J. Med. Chem., 61:2680-2693, 2018

PubMed Abstract: We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit. The optimized compounds inhibit the DCN1-UBE2M protein-protein interaction in our TR-FRET binding assay and inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay. The optimized compounds bind to DCN1 and selectively reduce steady-state levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell line. Ultimately, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers.

PubMed: 29547696
DOI: 10.1021/acs.jmedchem.7b01277

実験手法

X-RAY DIFFRACTION (1.05 Å)