Small Molecule BCL6 Inhibitors as Therapeutic Agents for B-Cell Lymphomas

Background & Unmet Need

• Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center (GC) reaction
• BCL6 is a transcriptional repressor involved in B-cell development
• BCL6 is also a key oncogene in many types of DLBCL, including GC B-cell (GCB)-DLBCL and Activated B-cell (ABC)-DLBCL, a class of DLBCLs that responds poorly to current therapies
• BCL6 is also expressed in follicular lymphomas (FL) and may be required for FL tumor cell survival
• Although protein-protein interactions are difficult to target with small molecules, BCL6 can be targeted via its highly specific BTB domain groove motif
• However, current BCL6 inhibitors are limited by their low binding affinity and therefore low efficacy
• Unmet Need: A small molecule inhibitor of BCL6 that is effective, specific, and non-toxic

Technology Overview

• The Technology: Small molecule inhibitor of BCL6 as a therapeutic candidate for B-cell lymphomas and other BCL6-dependent cancers
• In silico functional group mapping led to the design of improved small molecules which bind BCL6, disrupt formation of BCL6 repression complex, and induce de-repression of BCL6 target genes
• FX1 is highly specific, 10x more potent than endogenous co-repressors, and 100x more potent than the previous generation of BCL6 inhibitors
• FX1 enhances response to doxorubicin, including in chemotherapy-resistant ABC-DLBCLs
• PoC Data: Low, non-toxic doses of FX1 induced regression in 95% of established tumors in mice bearing GCB-DLBCL xenografts
• FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo

Technology Applications

• Therapeutic agent for the treatment of B-cell lymphomas, such as DLBCL and FL
• Therapeutic agent for the treatment of other malignancies expressing BCL6
• Combination therapy with cytotoxic agents, including for chemotherapy-resistant malignancies

Technology Advantages

• Superior potency and efficacy at lower concentrations and without toxicity
• High specificity since FX1 binds the BTB lateral groove motif unique to BCL6 and not conserved in other BTB proteins
• Synergistic effect in combination with chemotherapy
• Favorable pharmacokinetics in vitro and in vivo
• High water solubility and good stability