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Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction

Ding, Jian, Li, Guo, Liu, Hejun, Liu, Lulu, Lin, Ying, Gao, Jingyan, Zhou, Guoqiang, Shen, Lingling, Zhao, Mengxi, Yu, Yanyan, Guo, Weihui, Hommel, Ulrich, Ottl, Johannes, Blank, Jutta, Aubin, Nicola, Wei, Yi, He, Hu, Sage, David, Atadja, Peter, Li, En, Jain, Rishi, Tallarico, John, Canham, Steve, Chiang, Yingling and Wang, He (2023) Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction. ACS Chemical Biology. ISSN 1554-89291554-8937


WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple processes and is also a prominent target for pharmacological inhibition in multiple disease such as cancer, aging and neurodegenerative disorders. Interaction between WDR5 and its various partners are essential for sustaining its function. Most drug-discovery efforts center on the WIN 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 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.

Item Type: Article
Date Deposited: 25 Jan 2023 00:45
Last Modified: 25 Jan 2023 00:45


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