2. Academic Validation
  3. Identification and validation of WDR5 WIN-site ligands via DNA-encoded chemical library screening

Identification and validation of WDR5 WIN-site ligands via DNA-encoded chemical library screening

  • Bioorg Chem. 2024 Nov 22:154:107948. doi: 10.1016/j.bioorg.2024.107948.
Baoli Ding 1,  Li Lu 1,  Jiawen Hu 1,  Rongtian Zhang 1,  Feifan Wang 2,  Zhesheng Zhou 1,  Yushen Lin 1,  Chenghao Pan 3,  Yihui Zhou 1,  Bo Yang 4,  Cheng-Liang Zhu 5,  Chun Zhou 6,  Ji Cao 7
Affiliations

Affiliations

  • 1 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
  • 2 School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, PR China.
  • 3 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China.
  • 4 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou 310058, PR China; School of Medicine, Hangzhou City University, Hangzhou 310015, PR China.
  • 5 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China; Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, PR China. Electronic address: chengliangzhu@zju.edu.cn.
  • 6 School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, PR China. Electronic address: chunzhou@zju.edu.cn.
  • 7 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou 310058, PR China. Electronic address: caoji88@zju.edu.cn.
PMID: 39616835 DOI: 10.1016/j.bioorg.2024.107948
Abstract

WD repeat-containing protein 5 (WDR5) is a scaffolding protein involved in critical protein-protein interactions and a promising target for therapeutic development. Novel small-molecule ligands targeting WDR5 were identified using the DELopen platform, a free-access DNA-encoded chemical library (DEL) for academic research. Through off-DNA structure-activity relationship studies and photoaffinity labeling, two promising initial leads, DBL-6-13 and DBL-6-33, were identified as new Binders of WDR5. These compounds exhibited moderate to good binding affinities and were confirmed to bind the WIN-site through co-crystal structure analysis. Our findings demonstrate the utility of DEL technology in identifying ligands for challenging targets like WDR5, particularly within an academic research setting using the DELopen platform. The identified WDR5 ligands offer a foundation for further optimization and exploration as chemical probes for WDR5 research.

Keywords

DEL; DNA-encoded chemical library; Drug discovery; High-throughput screening; Small-molecule ligands; WDR5; WIN-site.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-169415
    WDR5抑制剂
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