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

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Protein oligomerization is a therapeutic target, but finding inducers is difficult.
• WD repeat domain 5 (WDR5) is implicated in various cellular processes.

Purpose of the Study:

• To develop a nanopore-based screening platform for identifying protein oligomerization inducers.
• To discover novel small molecules that modulate WDR5 oligomerization.
• To elucidate the mechanism of WDR5 oligomerization induced by small molecules.

Main Methods:

• Nanopore technology for high-throughput screening.
• Biochemical assays and cryo-electron microscopy (cryo-EM) for structural and mechanistic studies.
• Cellular assays to evaluate anti-tumor activity.

Main Results:

• Identified WZ-1 as a selective WDR5 oligomerization inducer using nanopore sensing.
• Elucidated the Catalytic Proximal Protein Oligomerization (CaPPO) mechanism involving WZ-1, WDR5, and disulfide bond formation.
• WZ-1 demonstrated potent anti-tumor activity by disrupting WDR5 interactions and downregulating target genes.

Conclusions:

• Established a nanopore-based platform for discovering protein oligomerization inducers.
• Validated CaPPO as a viable strategy for small-molecule drug design.
• WZ-1 shows therapeutic potential for cancer treatment by targeting WDR5.