Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent

Vianello, Paola; Botrugno, Oronza A.; Cappa, Anna; Zuffo, Roberto Dal; Dessanti, Paola; Mai, Antonello; Marrocco, Biagina; Mattevi, Andrea; Meroni, Giuseppe; Minucci, Saverio; Stazi, Giulia; Thaler, Florian; Trifiró, Paolo; Valente, Sérgio; Villa, Manuela; Varasi, Mario; Mercurio, Ciro

doi:10.1021/acs.jmedchem.5b01209

Cited by 74 publications

(71 citation statements)

References 67 publications

(125 reference statements)

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“…Among compounds 3 , the syntheses of 3 b , d – g were reported previously by us . The synthesis of 3 a was accomplished by coupling the commercially available 4‐{[(benzyloxy)carbonyl]amino}benzoic acid 7 with the tert ‐butyl [2‐(4‐aminophenyl)cyclopropyl]carbamate 8 in the presence of N ‐ethyl‐ N′ ‐(3‐ N , N ‐dimethylaminopropyl)carbodiimide (EDC) hydrochloride in dichloromethane (DCM), followed by cleavage of the tert ‐butoxycarbonyl (Boc)‐protected intermediate 9 with 4 M HCl solution in 1,4‐dioxane (Scheme A).…”

Section: Resultsmentioning

confidence: 99%

Tranylcypromine‐Based LSD1 Inhibitors: Structure‐Activity Relationships, Antiproliferative Effects in Leukemia, and Gene Target Modulation

et al. 2020

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LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying aroyl‐ and arylacetylamino (1 a–h), Z‐amino acylamino (2 a–o), or double‐substituted benzamide (3 a–n) residues at the C4 or C3 position of the phenyl ring. Further fragments obtained by chemical manipulation applied on the TCP scaffold (compounds 4 a–i) were also prepared. When tested against LSD1, most of 1 and 3 exhibited IC50 values in the low nanomolar range, with 1 e and 3 a,d,f,g being also the most selective respect to monoamine oxidases. In MV4‐11 AML and NB4 APL cells compounds 3 were the most potent, displaying up to sub‐micromolar cell growth inhibition against both cell lines (3 a) or against NB4 cells (3 c). The most potent compounds in cellular assays were also able to induce the expression of LSD1 target genes, such as GFI‐1b, ITGAM, and KCTD12, as functional read‐out for LSD1 inhibition. Mouse and human intrinsic clearance data highlighted the high metabolic stability of compounds 3 a, 3 d and 3 g. Further studies will be performed on the new compounds 3 a and 3 c to assess their anticancer potential in different cancer contexts.

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Section: Resultsmentioning

confidence: 99%

Tranylcypromine‐Based LSD1 Inhibitors: Structure‐Activity Relationships, Antiproliferative Effects in Leukemia, and Gene Target Modulation

et al. 2020

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“…Our contribution in this field was to prepare novel LSD1/HDAC dual inhibitors by the introduction of the HDAC inhibiting hydroxamate or benzamide side chain at the phenyl ring of tranylcypromine 24 , where we previously inserted various amide or amino acid substituents that highly improved the LSD1 inhibitory potency of 24 itself . Size exclusion chromatography revealed a stable association of the HDAC1:LSD1:CoREST ternary complex with 1:1:1 stoichiometry.…”

Section: The Mtdl Approachmentioning

confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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“…2), 85 and ( S ,1 S ,2 R )-MC2580/14e 86 (Table 2). A specific stereoisomer of an MC2584/13b derivative with a 4-methylpiperazine substituent was prepared and found to be orally active, with an IC 50 of 84 nM against LSD1 87 . In addition, the stereochemistry of MC2580/14e was simplified by preparation of derivatives in which the chiral amino acid moiety was replaced with an N -carbobenzyloxy-proline residue (PDB ID: 4UXN) and with pyrrole or indole derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…2) inhibits LSD2 with a K i of 26 µM and LSD1 with a K i of 2.5 µM 133,134 . A series of MC2584/13b benzamide-cyclopropylamine derivatives was also tested in vitro against LSD1, LSD2, MAO-A, and MAO-B 87 . Whereas all the tested derivatives exhibited submicromolar IC 50 values for LSD1 (20–300 nM), their potencies for LSD2 ranged from 4.3 to 75 µM; that is, they were specific for LSD1 over LSD2.…”

Section: Introductionmentioning

confidence: 99%

Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

Niwa¹,

Umehara

2017

Epigenetics

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Until 2004, many researchers believed that protein methylation in eukaryotic cells was an irreversible reaction. However, the discovery of lysine-specific demethylase 1 in 2004 drastically changed this view and the concept of chromatin regulation. Since then, the enzymes responsible for lysine demethylation and their cellular substrates, biological significance, and selective regulation have become major research topics in epigenetics and chromatin biology. Many cell-permeable inhibitors for lysine demethylases have been developed, including both target-specific and nonspecific inhibitors. Structural understanding of how these inhibitors bind to lysine demethylases is crucial both for validation of the inhibitors as chemical probes and for the rational design of more potent, target-specific inhibitors. This review focuses on published small-molecule inhibitors targeted at the two flavin adenine dinucleotide-dependent lysine demethylases, lysine-specific demethylases 1 and 2, and how the inhibitors interact with the tertiary structures of the enzymes.

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Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent

Cited by 74 publications

References 67 publications

Tranylcypromine‐Based LSD1 Inhibitors: Structure‐Activity Relationships, Antiproliferative Effects in Leukemia, and Gene Target Modulation

Tranylcypromine‐Based LSD1 Inhibitors: Structure‐Activity Relationships, Antiproliferative Effects in Leukemia, and Gene Target Modulation

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

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