Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery

Area of Science:

• Cancer epigenetics
• Molecular biology
• Drug discovery

Background:

• Epigenetic dysregulation is implicated in cancers, including leukemia.
• The role of Tudor domains in leukemia progression and therapy is largely unknown.

Purpose of the Study:

• To investigate the role of Tudor domains in leukemia.
• To develop a novel drug discovery strategy for leukemia therapy.

Main Methods:

• Conducted a CRISPR screen targeting Tudor domains.
• Integrated CRISPR tiling scan with compound docking and molecular dynamics simulation (CRISPR-SADD).
• Identified and characterized a novel SGF29 inhibitor.

Main Results:

• Identified SGF29 as a key factor in H3K9 acetylation, ribosomal gene expression, and leukemogenesis.
• Developed the CRISPR-Scan Assisted Drug Discovery (CRISPR-SADD) platform.
• Discovered a lead inhibitor targeting SGF29's Tudor domain with demonstrated efficacy in leukemia models.

Conclusions:

• SGF29 is a critical epigenetic regulator in leukemia.
• CRISPR-SADD is a powerful platform for de novo drug discovery.
• Targeting SGF29 offers a promising therapeutic strategy for leukemia.