Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

Abstract

Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role in hematopoiesis and was identified as a dependency factor in leukemia stem cell populations. Therefore, we investigated the consequences of inhibiting KDM1A in a panel of cell lines representing all acute myelogenous leukemia (AML) subtypes using selective, reversible and irreversible KDM1A smallmolecule inhibitors. Cell models of AML, CML, and T-ALL were potently affected by KDM1A inhibition, and cells bearing RUNX1-RUNX1T1 (AML1-ETO) translocations were especially among the most sensitive. RNAi-mediated silencing of KDM1A also effectively suppressed growth of RUNX1-RUNX1T1-containing cell lines. Furthermore, pharmacologic inhibition of KDM1A resulted in complete abrogation of tumor growth in an AML xenograft model harboring RUNX1-RUNX1T1 translocations. We unexpectedly found that KDM1A-targeting compounds not only inhibited the catalytic activity of the enzyme, but evicted KDM1A from target genes. Accordingly, compound-mediated KDM1A eviction was associated with elevated levels of local histone H3 lysine 4 dimethylation, and increased target gene expression, which was further accompanied by cellular differentiation and induction of cell death. Finally, our finding that KDM1A inhibitors effectively synergize with multiple conventional as well as candidate anti-AML agents affords a framework for potential future clinical application. Cancer Res; 76(7); 1975-88. Ó2016 AACR.

Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC

“…Treatment of AML cell lines and a xenograft model with the cyclopropylaminebased irreversible KDM1A inhibitor RN-1 led to inhibition of tumor cell growth and increased cellular differentiation. 27 Another study found the combination treatment of an irreversible KDM1A inhibitor T-3775440 with the neural precursor cell expressed, developmentally down-regulated 8-activating enzyme inhibitor pevonedistat resulted in synergistic growth inhibition of AML cells and improved survival in a tumor xenograft model of AML. 28 The KDM1A inhibitor ORY-1001 was investigated in a multicenter phase I study in relapsed or refractory acute leukemia.…”

Histone demethylase LSD1 controls the phenotypic plasticity of cancer cells

“…Upon LSD1 inhibition and ATRA treatment, the expression of genes associated with myeloid differentiation was upregulated with a concomitant increase of H3K4me2 levels at these genes. LSD1 inhibitor exerts synergistic effects with other anti‐cancer agents, such as Ara‐C or an inhibitor of H3K27 methyltransferase, on the induction of AML cell death, indicating the multifaceted function of LSD1 . Moreover, Harris et al .…”

“…LSD1 inhibitor exerts synergistic effects with other anti-cancer agents, such as Ara-C or an inhibitor of H3K27 methyltransferase, on the induction of AML cell death, indicating the multifaceted function of LSD1. (39) Moreover, Harris et al report the contribution of LSD1 in maintaining stem cell properties in a subtype of AML harboring an MLL gene translocation. (40) Increased expression of LSD1 was detected in MLL-mutant leukemia cells, especially in cells expressing the MLL-AF9 fusion protein, which acts as an oncogenic transcriptional regulator.…”

Drug Design Concepts for LSD1‐Selective Inhibitors

“…Meanwhile, several reversible LSD1 inhibitors have been reported in recent years, most of which were discovered by basic strategies for drug discovery such as high‐throughput screening and hit‐to‐lead optimization. As shown in Figure , reversible inhibitors 8–11 are structurally diverse [e. g., N ′ ‐(1‐phenylethylidene) benzohydrazides in 8 , dithiocarbamates in 9 , 3, 5‐diamino‐1,2,4‐triazole in 10 , and pyridine in 11 ] . Reversible LSD1 inhibitors also show various inhibition types, such as competitive in 10 , non‐competitive in 8 , and cofactor competitive in 9 , which were revealed by enzymology analysis.…”