Design synthesis and biological evaluation of novel BCL6/GSPT1 degrader as anti-DLBCL agent.

BCL6 is regarded as a promising therapeutic target for diffuse large B-cell lymphoma. However, most of the current BCL6 inhibitors and degraders have demonstrated limited antitumor efficacy when used as monotherapy. We hypothesized that developing multitarget degraders capable of simultaneously degrading multiple lymphoma-driving proteins might yield superior anti lymphoma activity. In this study, based on the BCL6 inhibitor BI3812, we designed and identified a dual-target degrader A5, which effectively degraded both BCL6 and GSPT1. A5 induced the degradation of BCL6 and GSPT1 in a time- and concentration-dependent manner, restored the expression of BCL6-regulated genes, and significantly promoted DNA damage in Farage cells. Consequently, A5 exhibited enhanced antiproliferative activity compared to the BCL6 inhibitor BI3812 and the BCL6 degrader BI3802, along with induction of cell cycle arrest and apoptosis. Furthermore, A5 significantly downregulated BCL6 and GSPT1 protein levels in vivo. Thus, this study provides a solid foundation for the development of novel multitarget BCL6 degraders with improved anti-lymphoma potential.