Identification of JL1037 as a novel, specific, reversible lysine-specific demethylase 1 inhibitor that induce apoptosis and autophagy of AML cells

Abstract

Lysine-specific demethylase 1 (LSD1) has been recognized as a potential therapeutic target for acute myeloid leukemia (AML). Herein, we identified a novel LSD1 inhibitor, JL1037, via Computer Aided Drug Design technology. JL1037 is a potent, selective and reversible LSD1 inhibitor with IC50s of 0.1 μM and >1.5 μM for LSD1 and monoamine oxidases A/B (MAO-A/B), respectively. Treatment of THP-1 and Kasumi-1 cell lines with JL1037 resulted in dose dependent accumulation of H3K4me1 and H3K4me2, the major substrates of LSD1, as well as inhibition of cell proliferation, blockade of cell cycle and induction of apoptosis. Further investigations demonstrated that JL1037 could upregulate cell cycle-related proteins P21, P57, pro-apoptotic protein Bax and downregulate anti-apoptosis proteins Bcl-2 and Bcl-XL. JL1037 appeared to activate autophage response in AML cell lines as well as primary cells from AML patients by increasing LC3-II expression and the formation of autophagosomes and autolysosomes in cytoplasm. Co-treatment with autophagy inhibitor chloroquine (CQ) enhanced JL1037-induced cell apoptosis. Moreover, daily intravenous administration of JL1037 tended to reduce tumor burden and prolong the survival of t(8;21) leukemia mice. In conclusion, JL1037 exhibited potent anti-leukemia effect and could be a potential therapeutic agent for AML treatment.

LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML

“…It is clear that LSD1 inhibition may have antileukemic efficacy against multiple AML subtypes driven by other mutations. [36][37][38] For this reason, it will be important to determine if similar effects on chromatin dynamics are seen and whether similar TF networks are engaged when non-MLL-rearranged AML cells are treated with GSK-LSD1. Consistent with this, a previous study demonstrated that knockdown of PU.1 modulates LSD1 inhibitor sensitivity in a non-MLL-rearranged human acute erythroid leukemia cell line.…”

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

“…These results strongly supported the idea that the autophagy pathway regulated by LSD1 was independent of BECN-1 and different from the autophagy process induced by starvation. Inhibition of LSD1 in AML cells, using the JL1037 inhibitor, provoked LC3B-II and autophagosome accumulation [72]. Moreover, combination of JL1037 with CQ favored apoptosis in this cell model.…”

“…Moreover, a high expression of LSD1 in neuroblastoma was correlated with poor prognosis [74]. Similarly, the expression of LSD1 was also increased in acute myeloid leukemia [72]. In neuroblastoma SH-SY5Y cells, inhibition of LSD1, using chemical inhibitors (TCP or SP2509), blocked LSD1 recruitment onto the SESN2 (sestrin2) promoter and induced its expression.…”

Biology of DNMT3 and LSD1 inhibition in acute myeloid leukaemia (AML)

“…In leukaemia cell lines, there appears to be synergism between HDAC and LSD1 inhibitors which supports a clinical trial for further exploration [15]. More recently, a study describes a novel, specific, reversible lysine-specific demethylase 1 inhibitor JL1037 that induce apoptosis in cell lines as well as primary cells from AML patients [60]. Preclinical data have prompted multiple phase I trials using either irreversible LSD1 inhibitors such as GSK2879552 as a single agent or tranylcypromine in combination with ATRA (NCT02177812 and NCT02261779 at https://clinicaltrials.gov/, respectively).…”