2. Academic Validation
  3. Catalytic Proximal Protein Oligomerization as an Anti-Tumor Strategy Targeting WDR5

Catalytic Proximal Protein Oligomerization as an Anti-Tumor Strategy Targeting WDR5

  • Nat Commun. 2026 Mar 13;17(1):3879. doi: 10.1038/s41467-026-70409-z.
Yizheng Fang # 1,  Li Jiang # 1 2,  Feifan Wang 3,  Yihui Zhou 1,  Jie Cen 1,  Yuxin Yang 4,  Haiyang Wang 1,  Qi Chen 1,  Yushen Lin 1,  Tingting Wang 1 2,  Hongxia Xu 1 2,  Yongping Yu 1,  Chengliang Zhu 1 2 5,  Qiaojun He 1 3 5 6 7,  Bo Yang 1 2 6 7 8,  Chun Zhou 9,  Wenteng Chen 10,  Longhua Tang 11,  Ji Cao 12 13 14 15 16 17
Affiliations

Affiliations

  • 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2 Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, China.
  • 3 School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 State Key Laboratory of Extreme Optics and Instrumentation, College of Optical Science and Engineering, Zhejiang University, Hangzhou, China.
  • 5 Cancer Center, Zhejiang University, Hangzhou, China.
  • 6 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China.
  • 7 Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, China.
  • 8 School of Medicine, Hangzhou City University, Hangzhou, China.
  • 9 School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 10 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
  • 11 State Key Laboratory of Extreme Optics and Instrumentation, College of Optical Science and Engineering, Zhejiang University, Hangzhou, China. [email protected].
  • 12 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
  • 13 Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, China. [email protected].
  • 14 Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  • 15 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China. [email protected].
  • 16 Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, China. [email protected].
  • 17 School of Medicine, Hangzhou City University, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41820364 DOI: 10.1038/s41467-026-70409-z
Abstract

Inducing protein oligomerization holds therapeutic promise, yet identifying or rationally designing effective inducers remains challenging. In this study, we leverage nanopore technology to screen small molecules capable of modulating WD repeat domain 5 (WDR5) protein oligomerization and uncover a oligomerization mechanism which we term Catalytic Proximal Protein Oligomerization (CaPPO). Nanopore sensing enabled rapid identification of WZ-1, a selective WDR5 oligomerization inducer, from our in-house compound library. Biochemical and cryo-EM analyses reveal that WZ-1 binds the WBM site of WDR5 through its 2-aminothiazole moiety, reacts with Cys248 to form an intramolecular disulfide, and, through N-terminal tail-induced proximity of WDR5 molecules, triggers oligomerization via thio-disulfide exchange. Structure-activity relationship studies indicate that the disulfide motif within WZ-1 acts as a molecular scout initiating oligomerization. In cellular assays, WZ-1 exhibits potent anti-tumor activity by disrupting WDR5 interactions at both WIN and WBM sites, leading to transcriptional downregulation of target genes. Collectively, this work not only establishes a nanopore-based screening platform for identifying protein oligomerization inducers, but also validates CaPPO as a promising small-molecule design strategy for therapeutic development.

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