Fragment-Based Discovery of AF9 YEATS Domain Inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• YEATS family proteins, including ENL and AF9, regulate chromatin structure and gene transcription.
• Chromosomal translocations involving ENL are oncogenic drivers in leukemia.
• Existing ENL YEATS domain inhibitors have shown limited efficacy across various cancer cell lines.

Purpose of the Study:

• To identify novel inhibitors targeting the AF9 YEATS domain.
• To design and synthesize new chemotypes of AF9 YEATS domain inhibitors.
• To evaluate the antiproliferation activity of these novel inhibitors in cancer cells.

Main Methods:

• NMR fragment-based screening against the AF9 YEATS domain.
• Structure-guided design and synthesis of ten novel inhibitors.
• Affinity assays and complex structural analysis.
• Antiproliferation assays in AF9-sensitive HGC-27 cells.

Main Results:

• Four initial hits were identified through fragment screening.
• Ten novel inhibitors with new chemotypes were synthesized.
• Structural analysis revealed an additional hydrogen bond formed by the new inhibitors with AF9.
• The synthesized inhibitors demonstrated antiproliferation activity in AF9-sensitive HGC-27 cells, consistent with CRISPR study phenotypes.

Conclusions:

• Novel AF9 YEATS domain inhibitors with unique structural features have been developed.
• These inhibitors exhibit promising antiproliferation activity against AF9-sensitive cancer cells.
• The findings provide a foundation for structure-based optimization towards potent AF9 YEATS inhibitors for precise cancer therapy.