6BG5
Structure of 1-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(1-propylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)urea bound to DCN1
Summary for 6BG5
| Entry DOI | 10.2210/pdb6bg5/pdb |
| Descriptor | Endolysin, DCN1-like protein 1 chimera, N-[(2H-1,3-benzodioxol-5-yl)methyl]-N-(1-propylpiperidin-4-yl)-N'-[3-(trifluoromethyl)phenyl]urea (3 entities in total) |
| Functional Keywords | e3 ligase, hydrolase, ligase-inhibitor complex, ligase/inhibitor |
| Biological source | Enterobacteria phage T4 More |
| Total number of polymer chains | 1 |
| Total formula weight | 44770.85 |
| Authors | Guy, R.K.,Schulman, B.A.,Scott, D.C.,Hammill, J.T. (deposition date: 2017-10-27, release date: 2018-09-26, Last modification date: 2023-10-04) |
| Primary citation | 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 Cited by 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: 29547696DOI: 10.1021/acs.jmedchem.7b01277 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.1 Å) |
Structure validation
Download full validation report
