A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The BCL6 transcriptional repressor is a primary oncogene implicated in diffuse large B cell lymphoma (DLBCL).
• Targeting BCL6 offers a promising therapeutic strategy for DLBCL treatment.

Purpose of the Study:

• To identify and characterize low-molecular-weight compounds that inhibit BCL6 function.
• To evaluate the therapeutic potential of a novel BCL6 inhibitor in DLBCL models.

Main Methods:

• Computer-aided drug design and functional assays were employed to discover BCL6 inhibitors.
• X-ray crystallography and NMR were used to determine the binding mode of the identified compound.
• In vitro and in vivo assays assessed the compound's efficacy and toxicity in DLBCL cell lines, patient samples, and xenotransplantation models.

Main Results:

• A novel compound was identified that binds to the BCL6 BTB domain, disrupting BCL6/corepressor complexes.
• The compound demonstrated the ability to induce BCL6 target gene expression and selectively kill BCL6-positive DLBCL cell lines.
• Preclinical studies showed the compound to be non-toxic, potently suppress DLBCL tumors in vivo, and eliminate primary human DLBCL cells.

Conclusions:

• The identified compound represents a potential therapeutic agent for BCL6-driven DLBCL.
• Targeting the BCL6 BTB domain offers a viable strategy for developing novel DLBCL treatments.
• This study validates a drug discovery approach for targeting oncogenic transcriptional repressors.