Reversible Inhibitors of LSD1 as Therapeutic Agents in Acute Myeloid Leukemia: Clinical Significance and Progress to Date

Mould, Daniel P.; McGonagle, Alison E.; Wiseman, Daniel H.; Williams, Emma; Jordan, Allan M.

doi:10.1002/med.21334

Cited by 124 publications

(91 citation statements)

References 127 publications

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“…Numerous small molecule inhibitors of LSD1 have been developed and are in preclinical testing in several cancer types, including acute myeloid leukemia, breast cancer and neuroblastoma (35,36). Therefore, we sought to test whether LSD1 inhibition is able to attenuate gefitinib resistance induced by hypoxia.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Lü

Liu

Oeck

et al. 2018

Molecular Cancer Research

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The development of small-molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due, in part, to acquired resistance to conventional therapy. This study, documents that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation. Following hypoxic growth conditions, HCC827 cells treated with gefitinib upregulated N- cadherin, Fibronectin and Vimentin expression and downregulated E-cadherin, characteristic of an epithelial-mesenchymal transition (EMT) which prior studies have linked to EGFR TKI resistance. Mechanistically, knockdown of the histone demethylases, LSD1 and PLU-1, prevented and reversed hypoxia-induced gefitinib resistance, with inhibition of the associated EMT, suggesting that LSD1 and PLU-1 play key roles in hypoxia-induced gefitinib resistance and EMT. Moreover, hypoxia-treated HCC827 cells demonstrated more aggressive tumor growth in vivo compared to cells grown in normoxia, but inhibition of LSD1 function by shRNA- mediated knockdown or by the small-molecular inhibitor, SP2509, suppressed tumor growth and enhanced gefitinib response in vivo. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through epigenetic change and coordination of EMT in NSCLC. This study suggests that combination of therapy with EGFR TKIs and LSD1 inhibitors may offer an attractive therapeutic strategy for NSCLCs.

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Section: Resultsmentioning

confidence: 99%

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Lü

Liu

Oeck

et al. 2018

Molecular Cancer Research

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“…During the revision of this manuscript, we noticed that scientists at GlaxoSmithKline found a structurally similar LSD1 inhibitor and presented its preliminary data in the 2013 American Association of Cancer Research annual meeting. 34,26b,27i …”

Section: Introductionmentioning

confidence: 99%

3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1

Zhou

Yao

et al. 2015

J. Med. Chem.

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Methylation of histone lysine residues plays important roles in gene expression regulation as well as cancer initiation. Lysine specific demethylase 1 (LSD1) is responsible for maintaining balanced methylation levels at histone H3 lysine 4 (H3K4). LSD1 is a drug target for certain cancers, due to important functions of methylated H3K4 or LSD1 overexpression. We report the design, synthesis and structure activity relationships of 3-(piperidin-4-ylmethoxy)pyridine containing compounds as potent LSD1 inhibitors with Ki values as low as 29 nM. These compounds exhibited high selectivity (>160×) against related monoamine oxidase A and B. Enzyme kinetics and docking studies suggested they are competitive inhibitors against a dimethylated H3K4 substrate and provided a possible binding mode. The potent LSD1 inhibitors can increase cellular H3K4 methylation and strongly inhibit proliferation of several leukemia and solid tumor cells with EC50 values as low as 280 nM, while they had negligible effects on normal cells.

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“…For example, CoREST paralogs (CoREST2/RCOR2 and CoREST3/RCOR3) were recently shown to alter KDM1A activity toward nucleosomal substrates as assessed by their DNA binding ability and also affected catalytic efficiency toward peptide substrates. 17,50,51 Because we are utilizing the minimal peptide substrate (H3K4me2 1–21 ) in these studies, and inhibitor potency seems to be unaffected by the presence of CoREST in vitro , 23,52 we moved forward with our investigation using isolated KDM1A.…”

Section: Discussionmentioning

confidence: 99%

Lysine-Specific Demethylase 1A (KDM1A/LSD1): Product Recognition and Kinetic Analysis of Full-Length Histones

et al. 2016

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Lysine-specific demethylase 1A (KDM1A/LSD1) is a FAD-dependent enzyme that catalyzes the oxidative demethylation of histone H3K4me1/2 and H3K9me1/2 repressing and activating transcription, respectively. Although the active site is expanded compared to that of members of the greater amine oxidase superfamily, it is too sterically restricted to encompass the minimal 21-mer peptide substrate footprint. The remainder of the substrate/product is therefore expected to extend along the surface of KDM1A. We show that full-length histone H3, which lacks any posttranslational modifications, is a tight-binding, competitive inhibitor of KDM1A demethylation activity with a Ki of 18.9 ± 1.2 nM, a value that is approximately 100-fold higher than that of the 21-mer peptide product. The relative H3 affinity is independent of preincubation time, suggesting that H3 rapidly reaches equilibrium with KDM1A. Jump dilution experiments confirmed the increased binding affinity of full-length H3 was at least partially due to a slow off rate (koff) of 1.2 × 10−3 s−1, corresponding to a half-life (t1/2) of 9.63 min, and a residence time (τ) of 13.9 min. Independent affinity capture surface plasmon resonance experiments confirmed the tight-binding nature of the H3/KDM1A interaction, revealing a Kd of 9.02 ± 2.3 nM, a kon of (9.3 ± 1.5) × 104 M−1 s−1, and a koff of (8.4 ± 0.3) × 10−4 s−1. Additionally, no other core histones exhibited inhibition of KDM1A demethylation activity, which is consistent with H3 being the preferred histone substrate of KDM1A versus H2A, H2B, and H4. Together, these data suggest that KDM1A likely contains a histone H3 secondary specificity element on the enzyme surface that contributes significantly to its recognition of substrates and products.

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Reversible Inhibitors of LSD1 as Therapeutic Agents in Acute Myeloid Leukemia: Clinical Significance and Progress to Date

Cited by 124 publications

References 127 publications

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1

Lysine-Specific Demethylase 1A (KDM1A/LSD1): Product Recognition and Kinetic Analysis of Full-Length Histones

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