Anti-leukemic properties of aplysinopsin derivative EE-84 alone and in combination with BH3 mimetic A-1210477

Although both the indole and N-benzyl moieties of aplysinopsins are known to possess anti-proliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests as well as analysis of differential toxicity in non-cancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against myeloid leukemia.

This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five and was responsible for the senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells likewise underwent morphological changes suggesting mitochondrial dysfunction, autophagy and ER stress as cellular stress responses. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor (A-1210477), against K562 and K562IR cells, highlighting the inhibition of anti-apoptotic Bcl-2 proteins as a promising therapeutic approach against chronic myeloid leukemia.