Tacedinaline

Despite the good options for the management of Diffuse large B‐cell lymphoma (DLBCL), a significant percentage of patients either do not respond to current treatments or relapse after a short time. Thus, a wider palette of targeted therapeutic strategies is needed. Histone deacetylases (HDACs) inhibitors have shown promising responses in B‐cell malignancies, but their off‐target effects limit their efficiency. Here, we investigated the use of novel targeted therapeutics against class I HDACs to specifically induce cell death in DLBCL cells. We show that a proteolysis targeting chimera (PROTAC) that combined HDAC inhibitor CI‐994 and an IAP ligand had a strong effect in killing different DLBCL cell lines, being more effective in doing so than CI‐994 on its own. Moreover, we show that this was concomitant with the induction of DNA damage and apoptosis. A proteomics screen showed that the mechanism of induction of cell death by this PROTAC likely depends on the simultaneous activation of pro‐apoptotic proteins (such as PARP‐1, PDCD6IP, DAPk1, TP53BP1, and CACYBP) and the inhibition of pro‐survival pathways. We conclude that eliminating class I HDACs with specific PROTACs could be an effective and precise strategy for treating DLBCL that should be further tested for their potential clinical relevance.Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.