Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Diffuse large B cell lymphomas (DLBCLs) originate from germinal center B cells.
• Activated B cell DLBCLs (ABC-DLBCLs) exhibit poor response to current therapies.
• Constitutive BCL6 oncogene expression is common in ABC-DLBCLs due to genetic alterations.

Purpose of the Study:

• To investigate the role of BCL6 in maintaining ABC-DLBCLs.
• To develop and evaluate small-molecule inhibitors targeting BCL6 for ABC-DLBCL therapy.

Main Methods:

• Utilized in silico drug design (SILCS) to create a BCL6 inhibitor (FX1).
• Assessed FX1's binding affinity, disruption of BCL6 repression complex, and target gene reactivation.
• Evaluated FX1's efficacy in preclinical models (xenografts) and human ABC-DLBCL specimens.

Main Results:

• FX1 inhibitor demonstrated 10-fold greater potency than endogenous BCL6 corepressors.
• FX1 disrupted the BCL6 repression complex and reactivated BCL6 target genes.
• Low doses of FX1 induced tumor regression in DLBCL xenografts and suppressed ABC-DLBCL cells in vitro and in vivo.

Conclusions:

• ABC-DLBCL is a BCL6-dependent malignancy.
• Rationally designed BCL6 inhibitors with high binding affinity represent a promising therapeutic strategy for ABC-DLBCL.