Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• B-cell lymphoma 6 (BCL6) is a transcriptional repressor often dysregulated in lymphoid cancers.
• BCL6 interacts with corepressors, presenting a target for therapeutic intervention.
• Targeting BCL6 protein-protein interactions is a promising drug development strategy.

Purpose of the Study:

• To develop and characterize a novel, irreversible inhibitor of BCL6.
• To evaluate the efficacy and mechanism of action of the new inhibitor, TMX-2164.
• To compare the advantages of covalent BCL6 inhibition over reversible methods.

Main Methods:

• Design and synthesis of an irreversible BCL6 inhibitor, TMX-2164, utilizing a sulfonyl fluoride moiety.
• Characterization of TMX-2164's covalent reaction with Tyrosine 58 in the BCL6 lateral groove.
• Assessment of inhibitory activity, target engagement, and antiproliferative effects in cellular models.

Main Results:

• TMX-2164 demonstrates significantly enhanced inhibitory activity compared to its reversible precursor.
• The inhibitor exhibits sustained target engagement and antiproliferative effects.
• TMX-2164 functions as a tyrosine-directed covalent inhibitor of BCL6.

Conclusions:

• TMX-2164 represents a novel irreversible BCL6 inhibitor with superior properties.
• Tyrosine-directed covalent inhibition offers advantages over reversible targeting for BCL6.
• This approach holds potential for developing new therapies for BCL6-driven malignancies.