The novel CELMoD CC-92480 has potent and broad activity against TCLs associated with selective degradation of IKZF1 and ZFP91. (A) Western blot in TCL lines upon exposure to 1 μM len, pomalidomide (pom), CC-220, or CC-92480 for 24 hours. (B) Western blot in SUP-M2 cells with dox-induced knockout of IKZF1 and ZFP91. (C-D) Cell count and percent PI⁺ in SUP-M2 cells with dox-induced knockout of IKZF1, ZFP91, or double knockout (DKO). Shown in (D) is cell number at day 4 relative to no dox. The experiment was performed in triplicate and replicated twice. Data are presented as mean plus or minus SD. Comparisons are by 2-tailed Student t test. (E) Correlation analysis of CRBN transcript expression levels with the extent of IKZF1 degradation by treatment of lenalidomide for 24 hours in TCL lines. Bottom, representative immunoblots show IKZF1 degradation in TCL lines treated with lenalidomide for 24 hours. (F) Relative fold changes in cell count across 20 TCL cell lines treated with indicated agents (1 μM) for 12 days compared to DMSO controls. (G) SUP-M2 cells were treated with 1 μM lenalidomide (left), pom (middle), CC-92480 (right), or DMSO for 5 hours, and protein abundance was quantified using TMT mass spectrometry–based proteomics. Significant changes were assessed by a moderated t test as implemented in the limma package, with the log₂ fold change (log₂FC) shown on the y-axis and −log₁₀(P values) on the x-axis. *P < .05; **P < .01; ***P < .001. TMT, tandem mass tag.