Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• B-cell lymphoma 6 (BCL6) is a key oncogenic driver in diffuse large B-cell lymphoma (DLBCL).
• Previous inhibitors faced limitations due to high topological polar surface area (TPSA), impacting cellular efflux and in vivo exposure.

Purpose of the Study:

• To optimize a tricyclic quinolinone series for enhanced BCL6 inhibition.
• To improve the cellular potency and in vivo pharmacokinetics of non-degrading BCL6 inhibitors.

Main Methods:

• Structure-based drug design and chemical synthesis of novel quinolinone derivatives.
• Pharmacokinetic studies to assess in vivo exposure and properties.
• In vitro cellular assays for BCL6 inhibition.
• In vivo efficacy testing in a lymphoma xenograft mouse model.

Main Results:

• Optimization focused on reducing molecular weight and TPSA to mitigate efflux issues.
• Discovery of CCT374705, a potent BCL6 inhibitor with improved pharmacokinetic properties.
• Modest in vivo efficacy demonstrated in a preclinical lymphoma model following oral administration.

Conclusions:

• Chemical optimization successfully addressed limitations of earlier BCL6 inhibitors.
• CCT374705 represents a promising candidate for further development in DLBCL treatment.
• Further studies are warranted to enhance the therapeutic potential of these BCL6 inhibitors.