IBL-202 and venetoclax inhibit PI3K signaling and downregulate expression of Bcl-2 family proteins. Expression of phosphorylated and total AKT and Bcl-xL (n = 8) (A) and phosphorylated and total Bad and NF-κB and c-Myc (n = 6) (B) was assessed by immunoblotting in primary CLL cells cultured in medium alone or cocultured with CD40L fibroblasts. CLL cells in coculture with fibroblasts were treated with IBL-202 (1 μM) or venetoclax (10 nM), alone or in combination. Levels of Mcl-1, Noxa, Bax, Bcl-2, Bcl-xL, and PARP were assessed by immunoblotting of primary CLL cells treated with IBL-202 (1 μM) and venetoclax (10 nM), alone or in combination (n = 6) (C), and ibrutinib (0.5 μM) or venetoclax (10 nM), alone or in combination (n = 3) (D). Representative data from 2 patient samples are shown in panels A-D. The values shown under each lane indicate the fold change in expression relative to an untreated control for each patient sample. (E) Histograms show the cumulative data of the Noxa/Mcl-1 expression ratio in CLL cells treated with IBL-202 (n = 6) or ibrutinib (n = 3), alone or in combination with venetoclax. ns, not significant.