8F1G

Crystal structure of human WDR5 in complex with compound WM662

Summary for 8F1G

• Entry DOI: 10.2210/pdb8f1g/pdb
• Descriptor: WD repeat-containing protein 5, (2S)-2-({(2S)-3-(3'-chloro[1,1'-biphenyl]-4-yl)-1-oxo-1-[(1H-tetrazol-5-yl)amino]propan-2-yl}oxy)propanoic acid, GLYCEROL, ... (6 entities in total)
• Functional Keywords: wdr5, wm662, myc, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 71295.29

Authors

Liu, H. (deposition date: 2022-11-05, release date: 2023-01-11, Last modification date: 2023-10-25)

Primary citation

Ding, J.,Li, G.,Liu, H.,Liu, L.,Lin, Y.,Gao, J.,Zhou, G.,Shen, L.,Zhao, M.,Yu, Y.,Guo, W.,Hommel, U.,Ottl, J.,Blank, J.,Aubin, N.,Wei, Y.,He, H.,Sage, D.R.,Atadja, P.W.,Li, E.,Jain, R.K.,Tallarico, J.A.,Canham, S.M.,Chiang, Y.L.,Wang, H.
Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction.
Acs Chem.Biol., 18:34-40, 2023

PubMed Abstract: WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple processes. It is also a prominent target for pharmacological inhibition in diseases such as cancer, aging, and neurodegenerative disorders. Interactions between WDR5 and various partners are essential for sustaining its function. Most drug discovery efforts center on the WIN (WDR5 interaction motif) site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe the discovery of novel WDR5 inhibitors for the other WBM (WDR5 binding motif) pocket on this scaffold protein, to disrupt WDR5 interaction with its binding partner MYC by high-throughput biochemical screening, subsequent molecule optimization, and biological assessment. These new WDR5 inhibitors provide useful probes for future investigations of WDR5 and an avenue for targeting WDR5 as a therapeutic strategy.

PubMed: 36594833
DOI: 10.1021/acschembio.2c00843

Experimental method

X-RAY DIFFRACTION (2.14 Å)