Catalytic Proximal Protein Oligomerization as an Anti-Tumor Strategy Targeting WDR5 - PubMed
3 hours ago
- #protein oligomerization
- #anti-tumor strategy
- #WDR5
- Inducing protein oligomerization is a promising therapeutic strategy, but identifying effective inducers is challenging.
- Nanopore technology was used to screen small molecules modulating WDR5 protein oligomerization, leading to the discovery of Catalytic Proximal Protein Oligomerization (CaPPO).
- WZ-1, a selective WDR5 oligomerization inducer, was identified through nanopore sensing from an in-house compound library.
- Biochemical and cryo-EM analyses showed WZ-1 binds the WBM site of WDR5, reacts with Cys248, and triggers oligomerization via thio-disulfide exchange.
- WZ-1 exhibits potent anti-tumor activity by disrupting WDR5 interactions at WIN and WBM sites, downregulating target genes.
- This study establishes a nanopore-based screening platform for protein oligomerization inducers and validates CaPPO as a therapeutic design strategy.