Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The BCL6 transcription factor drives oncogenesis in lymphoid malignancies like DLBCL.
• Targeting BCL6 interactions with transcriptional repressors can disrupt its oncogenic activity.

Purpose of the Study:

• To develop potent small molecules that inhibit BCL6 interactions with co-repressors.
• To investigate BCL6 degradation as a therapeutic strategy for DLBCL.

Main Methods:

• Structure-based drug design was employed to create BCL6 inhibitors.
• Cellular assays were used to assess compound efficacy, including gene expression changes and anti-proliferative effects.

Main Results:

• Highly potent compounds blocking BCL6-co-repressor interaction were developed.
• A subset of inhibitors induced BCL6 ubiquitylation and degradation.
• BCL6-degrading compounds showed superior induction of BCL6-repressed genes and anti-proliferative activity compared to non-degrading inhibitors.

Conclusions:

• The BTB domain of BCL6 is a druggable target.
• BCL6 degradation represents a promising therapeutic avenue for DLBCL.
• This approach may be applicable to other members of the BCL6 protein family.