A Small-Molecule BCL6 Inhibitor as an Anti-Proliferative Agent for Diffuse Large B-Cell Lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The B-cell lymphoma 6 (BCL6) transcription factor is crucial for germinal center (GC) formation.
• Dysregulation of BCL6 is implicated in the development of diffuse large B-cell lymphoma (DLBCL).
• Targeting the BCL6/corepressor interaction is a promising therapeutic strategy for lymphoma, but effective inhibitors are lacking.

Purpose of the Study:

• To discover and develop novel [1,2,4] triazolo[1,5-a] pyrimidine derivatives as inhibitors of the BCL6/SMRT interaction.
• To evaluate the efficacy and safety of the lead compound WK692 against DLBCL both in vitro and in vivo.

Main Methods:

• Synthesis and characterization of novel [1,2,4] triazolo[1,5-a] pyrimidine derivatives.
• In vitro assays to assess BCL6/SMRT interaction disruption, gene expression changes, DLBCL cell growth inhibition, and apoptosis induction.
• In vivo studies in animal models to evaluate tumor growth inhibition, GC formation, T cell populations, Ig affinity maturation, and toxicity.

Main Results:

• The lead compound WK692 directly bound to BCL6BTB and disrupted the BCL6BTB/SMRT interaction.
• WK692 activated BCL6 downstream gene expression, inhibited DLBCL growth, and induced apoptosis in vitro.
• In vivo, WK692 inhibited DLBCL growth without observable toxicity, suppressed GC formation, reduced follicular helper T cells, and impaired Ig affinity maturation.
• WK692 demonstrated synergistic effects when combined with EZH2 and PRMT5 inhibitors.

Conclusions:

• WK692 is a potent BCL6 inhibitor with significant anti-DLBCL activity.
• WK692 demonstrates a favorable safety profile in vivo.
• WK692 holds potential as a novel therapeutic agent for treating DLBCL, possibly in combination therapies.