Synergistic Interaction Between the LSD1 Inhibitor T-3775440 and the NEDD8-activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) Promotes Anti-Acute Myeloid Leukemia Effects. Homo sapiens

Lysine-specific demethylase 1A (LSD1) specifically demethylates di- and monomethylated histone H3K4 or K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation. We therefore tested the combination of these two agents in AML models.The combination treatment resulted in synergistic growth inhibition of AML cells, accompanied by enhanced transdifferentiation and suppression of the leukemic stem cell gene signature. Overall design: Total RNA obtained from cells treated treated with vehicle, 50 nM T-3775440, 1000 nM pevonedistat, or T-3775440 and pevonedistat in combination for 24 h in vitro. Effects of each compound or the combination on AML cells lines were compared that of DMSO-treated control.