Alraddadi A, Smalley JP, Alzahrani W, Saleh A, Al-Mansour F, He B, Cao TH, Jayne S, Dyer M, Hodgkinson JT, Jones DJL, Cowley SM, Macip S.
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.
Alraddadi A, Smalley JP, Alzahrani W, Saleh A, Al-Mansour F, He B, Cao TH, Jayne S, Dyer M, Hodgkinson JT, Jones DJL, Cowley SM, Macip S. Targeted Degradation of Class 1 HDACs With PROTACs is Highly Effective at Inducing DLBCL Cell Death. EJHaem. 2025 Aug 12;6(4):e70127. doi: 10.1002/jha2.70127. PMID: 40801055; PMCID: PMC12342057.