Novel Small Molecule DZ-865B Effectively Degrades BCL6, Promotes Apoptosis and Reduces Proliferation of Diffuse Large B-Cell Lymphoma Cells

Abstract B-cell lymphoma 6 (BCL6) is a transcriptional repressor essential for B lymphocyte differentiation and germinal center formation through its BTB structural domain. Overexpression of BCL6 is strongly implicated in the progression of diffuse large B-cell lymphoma (DLBCL), making it a promising therapeutic target. This study aims to identify a novel small molecule, synthesized via proteolysis-targeting chimeras (PROTACs), capable of degrading BCL6, thereby inhibiting DLBCL growth and providing a foundation for future preclinical studies. The expression of BCL6 in DLBCL was analyzed using The Cancer Genome Atlas (TCGA) database and the Human Protein Atlas. Western blotting assays confirmed BCL6 expression in tumor cell lines, leading to the identification of the small molecule compound DZ-865B. To evaluate DZ-865B’s in vitro efficacy, multiple assays were performed, including protein immunoblotting, immunofluorescence, quantitative PCR, EDU proliferation, and soft agar cloning assays. TCGA analysis revealed significant overexpression of BCL6 in DLBCL (P < 0.05), corroborated by immunohistological staining and western blotting. DZ-865B induced BCL6 degradation in DLBCL cell lines (OCI-LY-1 and SU-DHL-4) in a concentration- and time-dependent manner, reducing nuclear BCL6 levels. Notably, DZ-865B did not alter BCL6 mRNA levels but modulated downstream gene expression, leading to the activation of apoptosis pathway proteins and inhibition of DNA synthesis, effectively suppressing DLBCL cell growth. This study demonstrates that the small molecule DZ-865B targets and degrades BCL6 in DLBCL cells, promoting apoptosis and inhibiting cellular proliferation. These findings highlight DZ-865B as a potential therapeutic agent for diffuse large B-cell lymphoma.