Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1-Selective Inactivators

Itoh, Yukihiro; Aihara, Keisuke; Mellini, Paolo; Tojo, Takeo; Ota, Yosuke; Tsumoto, Hiroki; Solomon, V. Raja; Zhan, Peng; Suzuki, Miki; Ogasawara, Daisuke; Shigenaga, Akira; Inokuma, Takao; Nakagawa, Hidehiko; Miyata, Naoki; Mizukami, Tamio; Otaka, Akira; Suzuki, Takayoshi

doi:10.1021/acs.jmedchem.5b01323

Cited by 31 publications

(17 citation statements)

References 49 publications

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“…Because the SNAG domain of SNAIL1 can inhibit the binding of the H3 N-terminal peptide, 46 SNAIL1 peptide-based inhibitors have been explored. These peptidic inhibitors exhibit specificity for LSD1 over not only MAOs but also LSD2, 105 which is consistent with the fact that SNAIL1 binds to LSD2 with lower affinity than to LSD1 46 …”

Section: Introductionsupporting

confidence: 67%

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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Section: Introductionsupporting

confidence: 67%

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

Niwa¹,

Umehara

2017

Epigenetics

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“…[10][11][12][13][14] Enzymes that control post-translational modification of histone proteins in chromatin are often overexpressed in tumours and have been the focus of much research in this area. [15][16][17][18] One such class of enzymes is the histone deacetylases (HDACs). [19][20][21] Together with the histone acetylases, they control the extent of acetylation of ε-lysine residues within the histone core.…”

Section: Introductionmentioning

confidence: 99%

Perfluorinated HDAC inhibitors as selective anticancer agents

et al. 2017

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A series of potent histone deacetylase inhibitors is presented that incorporate alkyl or perfluorinated alkyl chains. Several new compounds show greater in vitro antiproliferative activity than the clinically approved inhibitor, SAHA. Furthermore, the new compounds show up to 5-fold greater activity against cancer cells than healthy cells. This selectivity is in contrast to SAHA, which is more active against the healthy cell line than the cancer cell line tested. Finally, we report an increase in activity for SAHA under mild hyperthermia, indicating that it could be an interesting candidate to use in combination with thermal therapy.

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“…11), which is being clinically tested for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in the United States and Australia (phase I/II). 45,46,144) Moreover, we identified some mechanism-based LSD1 inhibi- tors, including peptide-based LSD1 inhibitors [145][146][147][148] and the drug delivery molecules were applied to PCPA-drug conjugates, [149][150][151] which release drugs by LSD1 inhibition. Thus, we identified several LSD1 inhibitors by strategical design focusing on LSD1 catalytic mechanism.…”

Section: Lysine Methylation Modulators and Their Applicationmentioning

confidence: 99%

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Itoh

2020

CHEMICAL & PHARMACEUTICAL BULLETIN

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Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.

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Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1-Selective Inactivators

Cited by 31 publications

References 49 publications

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

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

Perfluorinated HDAC inhibitors as selective anticancer agents

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

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