What type of study is this?

This is a Quantitative Study study (also classified as: Animal Study).

October 2, 2025

Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma

Key Points

A19, a novel BCL6 PROTAC, induces potent degradation of BCL6, demonstrating significant antiproliferative effects.
A19 achieves a DC50 of 34 pM in OCI-LY1 cells, outperforming current BCL6-targeting agents like BI3802.
RNA-seq analysis indicates A19 and BI3802 induce similar changes in signaling pathways, confirming their mechanism of action.
Oral administration of A19 successfully inhibits tumor growth in vivo, showcasing its therapeutic potential against DLBCL.

Abstract

B-cell lymphoma 6 (BCL6) is a key transcriptional repressor implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). However, current BCL6-targeting agents demonstrate restricted efficacy in vitro and in vivo, and the underlying mechanism remains unclear. In this study, we identified A19 as a potent BCL6 PROTAC through comprehensive structure-activity relationship (SAR) analysis. A19 induces rapid and efficient BCL6 degradation (DC50 = 34 pM in OCI-LY1 cells) and displays superior antiproliferative activity compared to the molecular glue BI3802 across multiple DLBCL cell lines. In addition, RNA-seq profiling showed that A19 and BI3802 trigger comparable changes in signaling pathways, reflecting similar transcriptomic responses. Further, oral dosing of A19 led to BCL6 degradation and inhibition of tumor growth in vivo. Overall, A19 is a valuable chemical tool and a promising lead compound toward the development of BCL6-dependent DLBCL.

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