Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors

Nie, Zhe; Shi, Lihong; Lai, Chon; Severin, Christophe; Xu, Jiangchun; Rosario, Joselyn R. Del; Stansfield, Ryan; Cho, Robert W.; Kanouni, Toufike; Veal, James M.; Stafford, Jeffrey A.; Chen, Young K.

doi:10.1016/j.bmcl.2018.11.001

Cited by 10 publications

(8 citation statements)

References 19 publications

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“…7D). 66 Molecular modeling of compound 46 indicated that the cyanophenyl moiety closely approached FAD, while the cyano group was predicated to make a hydrogen bond with Lys661. The primary amino group formed polar interactions with Asp555, while the tolyl moiety was embedded into a hydrophobic cavity formed by Phe538, Leu677 and Trp695.…”

Section: Reversible Lsd1 Inhibitorsmentioning

confidence: 99%

“…In 2019, Nie et al reported imidazole-based reversible LSD1 inhibitors based on the structural features of GSK-690 toward the active cavity of LSD1, resulting in the identification of imidazole analogues (such as compound 46 ) with enhanced potency (IC 50 = 8 nM) (Figure D) . Molecular modeling of compound 46 indicated that the cyanophenyl moiety closely approached FAD, while the cyano group was predicated to make a hydrogen bond with Lys661.…”

Section: Reversible Lsd1 Inhibitorsmentioning

confidence: 99%

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Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

et al. 2021

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As a flavin adenine dinucleotide (FAD)-dependent monoamine oxidase, lysine specific demethylase 1 (LSD1/KDM1A) functions as a transcription coactivator or corepressor to regulate the methylation of histone 3 lysine 4 and 9 (H3K4/9), and it has emerged as a promising epigenetic target for anticancer treatment. To date, numerous inhibitors targeting LSD1 have been developed, some of which are undergoing clinical trials for cancer therapy. Although only two reversible LSD1 inhibitors CC-90011 and SP-2577 are in the clinical stage, the past decade has seen remarkable advances in the development of reversible LSD1 inhibitors. Herein, we provide a comprehensive review about structures, biological evaluation, and structure–activity relationship (SAR) of reversible LSD1 inhibitors.

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Section: Reversible Lsd1 Inhibitorsmentioning

confidence: 99%

Section: Reversible Lsd1 Inhibitorsmentioning

confidence: 99%

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

et al. 2021

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“…Compound 4 is a heteroaromatic imidazole-based structure. The potency of imidazole against LSD1 has previously been supported by the computational modelling of the binding interactions with the active site of LSD1 [53]. All five molecules were predicted to have high activity.…”

Section: Virtual Screeningmentioning

confidence: 83%

Machine-Learning-Enabled Virtual Screening for Inhibitors of Lysine-Specific Histone Demethylase 1

Zhou

Lee

et al. 2021

Molecules

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A machine learning approach has been applied to virtual screening for lysine specific demethylase 1 (LSD1) inhibitors. LSD1 is an important anti-cancer target. Machine learning models to predict activity were constructed using Morgan molecular fingerprints. The dataset, consisting of 931 molecules with LSD1 inhibition activity, was obtained from the ChEMBL database. An evaluation of several candidate algorithms on the main dataset revealed that the support vector regressor gave the best model, with a coefficient of determination (R2) of 0.703. Virtual screening, using this model, identified five predicted potent inhibitors from the ZINC database comprising more than 300,000 molecules. The virtual screening recovered a known inhibitor, RN1, as well as four compounds where activity against LSD1 had not previously been suggested. Thus, we performed a machine-learning-enabled virtual screening of LSD1 inhibitors using only the structural information of the molecules.

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“…As part of our research work toward the synthesis of heterocycles with broad biological activities [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 38 ], this work aims to synthesize a library of some new aromatic-centered homologues tethered with two different active motifs: 1,2,4-triazole-3-thione and 1,3,4-thiadiazole. The design is based upon the chemical study of LSD1 inhibitors [ 39 , 40 , 41 , 42 , 43 ] in Figure 1 through the molecular hybridization of a central aromatic system with pyridine, pyrimidine, and imidazole rings in compounds 1 – 4 . Compounds 5 – 9 are embedded with five-membered aromatic systems, triazole and thiadiazole, which show good affinity and potency against LSD1.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Benzene Homologues Tethered with 1,2,4-Triazole and 1,3,4-Thiadiazole Motifs Revealing Dual MCF-7/HepG2 Cytotoxic Activity with Prominent Selectivity via Histone Demethylase LSD1 Inhibitory Effect

Alsehli

Aljuhani

Ihmaid

et al. 2022

IJMS

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In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure–activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC50 range of 0.04–1.5 μM. Compounds 27, 23, and 22 were found to be the most active analogs with IC50 values of 0.046, 0.065, and 0.074 μM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity.

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Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors

Cited by 10 publications

References 19 publications

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

Machine-Learning-Enabled Virtual Screening for Inhibitors of Lysine-Specific Histone Demethylase 1

Design and Synthesis of Benzene Homologues Tethered with 1,2,4-Triazole and 1,3,4-Thiadiazole Motifs Revealing Dual MCF-7/HepG2 Cytotoxic Activity with Prominent Selectivity via Histone Demethylase LSD1 Inhibitory Effect

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