Discovery of highly potent and novel LSD1 inhibitors for the treatment of acute myeloid leukemia: structure-based virtual screening, molecular dynamics simulation, and biological evaluation

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by rapid disease progression and a substantial unmet need for novel therapeutic interventions. Among emerging epigenetic targets for AML treatment, lysine-specific demethylase 1 (LSD1) has garnered significant attention due to its critical role in the self-renewal of leukemia stem cells. Targeting LSD1 presents an innovative avenue for disrupting these cells and halting disease progression. To explore this opportunity, a multi-step integrated screening protocol was developed, encompassing pharmacophore modeling, docking screening, molecular dynamics simulation, and biological evaluation, aimed at identifying potent LSD1 inhibitors.

Through this systematic approach, six highly effective LSD1 inhibitors—designated LTMs 1-6—were discovered. Among them, LTM-1 demonstrated exceptional inhibitory activity against LSD1, with an IC50 value of 2.11 ± 0.14 nM, and exhibited remarkable selectivity, showing greater than 2370-fold preference for LSD1 over LSD2. This specificity underscores its potential therapeutic utility by minimizing off-target effects. Furthermore, LTM-1 displayed outstanding antitumor efficacy in both in vitro and in vivo models. In vitro, LTM-1 exerted potent anti-proliferative effects on LSD1-dependent MV-4-11 leukemia cells, with an IC50 value of 0.16 ± 0.01 μM. In vivo, LTM-1 treatment significantly curtailed tumor growth in MV-4-11 xenografted mice, demonstrating its therapeutic potential.

An encouraging aspect of LTM-1′s profile is its favorable safety characteristics Seclidemstat, as no significant alterations were observed in liver and kidney function indices during treatment. This suggests that LTM-1 may offer both efficacy and tolerability, making it a promising candidate for preclinical development. Collectively, these findings position LTM-1 as a leading compound for AML therapy, introducing a new strategy for designing selective and effective LSD1 inhibitors to address the challenges posed by this malignancy.