Fig. 1.

The MCL1-specific inhibitor S63845 actively kills human T-ALL cells and strongly synergizes with venetoclax. a Eleven human T-ALL cell lines were treated with serial dilutions of S63845. Cell viability was determined by Cell-Titer Glo assay after 72 h of treatment. b KOPT-K1 cells were treated with serial dilutions of venetoclax or S63845, alone or in combination. Cell viability was determined using Cell-Titer Glo after 48 h of treatment. c KOPT-K1 cells were treated with 500 nM venetoclax and 50 nM S63845, alone or in combination. Apoptosis was measured by annexin V/PI staining after 24 h of treatment. d Combination treatment of venetoclax and S63845 depicted as normalized isobolograms shows strong synergy between the two BH3 mimetics in KOPT-K1 cells. Calcusyn software was used to analyze combination data to produce the isobolograms normalized to the IC₅₀ of each drug. The cells were treated with the following serial dilutions of combination doses: venetoclax, from 5.5 nM to 4000 nM; and S63845, from 1.4 nM to 1000 nM for 48 h. A combination index (CI) of 1 indicates an additive effect, CI < 1 a synergistic effect and CI > 1 antagonism