Thieno[3,2-<i>b</i>]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure–Activity Relationship

Vianello, Paola; Sartori, Luca; Amigoni, Federica; Cappa, Anna; Fagà, Giovanni; Fattori, Raimondo; Legnaghi, Elena; Ciossani, Giuseppe; Mattevi, Andrea; Meroni, Giuseppe; Moretti, Loris; Cecatiello, Valentina; Pasqualato, Sebastiano; Romussi, Alessia; Thaler, Florian; Trifiró, Paolo; Villa, Manuela; Botrugno, Oronza A.; Dessanti, Paola; Minucci, Saverio; Vultaggio, Stefania; Zagarrí, Elisa; Varasi, Mario; Mercurio, Ciro

doi:10.1021/acs.jmedchem.6b01019

Cited by 63 publications

(78 citation statements)

References 43 publications

(69 reference statements)

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“…Very recently, Vianello et al initiated a high-throughput screening (HTS) campaign using a time-resolved fluorescence resonance energy transfer technology to identify new reversible LSD1 inhibitors ( Figure 9) [64,65]. The initial HTS of compound collection containing 34,000 small molecules using the time-resolved fluorescence resonance energy transfer assay led to the discovery of 115 hit compounds, of which compound 17 was prioritized for its acceptable biochemical data and high-potential derivatization.…”

Section: Glu 379mentioning

confidence: 99%

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Zhang

2017

Future Med. Chem.

112

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LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc. In this review, we briefly highlight recent advances of LSD1 inhibitors mainly covering the literatures from 2015 to 2017 and tentatively propose our perspectives on the design of new LSD1 inhibitors for cancer therapy.

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Section: Glu 379mentioning

confidence: 99%

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Zhang

2017

Future Med. Chem.

112

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“…This ionic interaction has been exploited previously by Vianello and coworkers. [33][34] The 3-fluoro-4-methoxyphenyl group sits in a channel formed by Trp695, Ile356, Leu677 and Leu693. The ether oxygen is predicted to make a hydrogen bonding interaction with Gln358, however, if the phenyl group were to flip then it could also potentially form a similar interaction with Asn535.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…[27][28][29][30][31][32] Recently, the discovery and optimization of a series of thieno[3,2b]pyrrole-5-carboxamides, and the crystal structures of quinazoline based reversible inhibitors has also been described. [33][34][35]…”

mentioning

confidence: 99%

Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1

Mould

Alli²,

Bremberg

et al. 2017

J. Med. Chem.

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Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1). A further scaffold modification to a (4-cyanophenyl)glycinamide (e.g., 29a) led to the development of compound 32, with a K value of 32 nM and an EC value of 0.67 μM in a surrogate cellular biomarker assay. Moreover, this derivative does not display the same level of hERG liability as observed with 1 and represents a promising lead for further development.

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“…Non-cofactor-based approaches have also had some success, although the exact binding mode has usually not been corroborated by X-ray crystallography. One recent exception reports the optimization of a bicyclic heterocyclic scaffold to provide nanomolar LSD1 inhibitors that occupy the substrate-binding pocket [71].…”

Section: (D) Nicotinamide Adenine Dinucleotidementioning

confidence: 99%

Epigenetic drug discovery: a success story for cofactor interference

Ganesan

2018

Phil. Trans. R. Soc. B

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Within the past two decades, seven epigenetic drugs have received regulatory approval and numerous other candidates are currently in clinical trials. Among the epigenetic targets are the writer and eraser enzymes that are, respectively, responsible for the reversible introduction and removal of structural modifications in the nucleosome. This review discusses the progress achieved in the design and development of inhibitors against the key writer and eraser pairs: DNA methyltransferases and Tet demethylases; lysine/arginine methyltransferases and lysine demethylases; and histone acetyltransferases and histone deacetylases. A common theme for the successful inhibition of these enzymes in a potent and selective manner is the targeting of the cofactors present in the active site, namely zinc and iron cations, -adenosylmethione, nicotinamide adenine dinucleotide, flavin adenine dinucleotide and acetyl Coenzyme A.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

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Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure–Activity Relationship

Cited by 63 publications

References 43 publications

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1

Epigenetic drug discovery: a success story for cofactor interference

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