Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors

Ota, Yosuke; Miyamura, Shin; Araki, M.; Itoh, Yukihiro; Yasuda, Shusuke; Masuda, Michiaki; Taniguchi, T; Sowa, Yoshihiro; Sakai, Toshiyuki; Itami, Kenichiro; Yamaguchi, Junichiro; Suzuki, Takayoshi

doi:10.1016/j.bmc.2017.12.045

Cited by 17 publications

(11 citation statements)

References 44 publications

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“…123,124) The other class is a family of Fe(II)/αketoglutarate (αKG)-dependent oxidases (KDM2-8). 125) So far, we have identified LSD1, 32,35,[126][127][128] KDM2/7, 129) and KDM5 31,[130][131][132] inhibitors by LBDD, SBDD, and strategic chemistry approaches. In this section, we discuss the discovery of LSD1 inhibitors based on SBDD, LBDD, and enzyme 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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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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“…Although the biological activities of 1 were moderate in the in vitro and cellular assays, there is potential for their improvement through future optimization studies of the PCPA moiety and/or the linker of 1. 17,18) Further studies on PDCs are currently in progress in our laboratory.…”

Section: Communication To the Editormentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of a Conjugate of 5-Fluorouracil and an LSD1 Inhibitor

Ota

Nakamura

Elboray

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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Prodrug approaches are useful for enhancing the efficacies and reducing the side effects of anticancer drugs. Previously, we proposed a prodrug strategy for targeting cancers overexpressing lysine-specific demethylase 1 (LSD1), namely, conjugates of trans-2-phenylcyclopropylamine (PCPA, an LSD1 inhibitor) and anticancer drugs. In this study, we applied this prodrug strategy to the anticancer agent 5-fluorouracil (5-FU). In vitro assays showed that the PCPA-5-FU conjugate (1) released 5-FU upon the inhibition of LSD1. Furthermore, the conjugate (1) exerted an antiproliferative effect on colon cancer HCT116 cells. Thus, the PCPA-5-FU conjugate (1) was able to function as a prodrug of 5-FU, activated by LSD1 inhibition, and provided a useful new lead structure for further development.

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“…Therefore, TGS could be a powerful strategy for drug discovery. Using TGS strategies, we have identified several epigenetic modulators including HDAC inhibitors,, SIRT inhibitors, and LSD1 inhibitors . In this section, we highlight the discovery of LSD1‐selective inhibitors using TGS strategies based on our original ideas.…”

Section: Drug Design For Lsd1‐selective Inhibitors Based On Target‐gumentioning

confidence: 99%

“…In addition, the optimization studies of a series of NCD38 ( 16d ) analogs were performed by another approach . We focused on the X‐lay structure of the complex of LSD1 with a histone H3‐based suicide peptide‐bearing N ‐propargyl moiety (Figure , PDB code: 2UXN) .…”

Section: Drug Design For Lsd1‐selective Inhibitors Based On Target‐gumentioning

confidence: 99%

Drug Design Concepts for LSD1‐Selective Inhibitors

Ota

Suzuki

2018

The Chemical Record

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Lysine‐specific demethylase 1 (LSD1) is one of the flavin‐dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1‐selective inhibitors using target‐guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1‐selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1‐selective inhibitors.

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Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors

Cited by 17 publications

References 44 publications

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

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

Design, Synthesis, and Biological Evaluation of a Conjugate of 5-Fluorouracil and an LSD1 Inhibitor

Drug Design Concepts for LSD1‐Selective Inhibitors

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