Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators

Zhan, Peng; Itoh, Yukihiro; Suzuki, Takayoshi; Liu, Xinyong

doi:10.1021/acs.jmedchem.5b00229

Cited by 49 publications

(27 citation statements)

References 95 publications

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“…In our study, JAKi selectivity was assayed by measuring JAK/STAT phosphorylation and cytokine release using human innate immune cells. Discrepancies may be observed in the impact and isoform selectivity of JAKi depending on the cell lineages used and cytokines measured in different assay systems [29]. Further preclinical investigations and clinical studies will be required to assess the biological impact and clinical benefit of pan-JAK or JAK isoform-selective inhibition.…”

Section: Discussionmentioning

confidence: 99%

JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells

Fujita¹,

Matsuoka²,

Temmoku³

et al. 2020

Preprint

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Background: Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines. Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA. However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors. We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells.Results: Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400nM) in THP-1 cells. Whereas compared with barcitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations ( < 100nM). All JAKi inhibited GM-CSF-induced IL-1b production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1b production were larger compared to those of tofacitinib or upadacitinib at lower concentrations ( < 100nM). Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils.Conclusion: We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells. Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi. in the inhibition of JAK2 signaling pathways.

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Section: Discussionmentioning

confidence: 99%

JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells

Fujita¹,

Matsuoka²,

Temmoku³

et al. 2020

Preprint

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“…Cofactor, C. (C) Construction of a compound library by using click reaction, followed by screening for the identification of the hit compounds. discovery methodologies based on chemical ideas, e.g., drug design based on enzyme catalytic mechanism, 37,38) compound library construction by click chemistry, [39][40][41] and application of N + -C-H•••O hydrogen bond to drug design 42,43) (Fig. 2).…”

Section: Fig 2 Strategic Chemistry Approaches For Identification Ofmentioning

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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“…Target‐guided synthesis (TGS) is a method that allows target enzymes to synthesize their own inhibitors . The inhibitors identified by TGS are expected to show strong activity and high target selectivity because they are synthesized by a specific reaction (catalytic reaction in the case of LSD1 inhibitors) and/or in specific pockets of a target enzyme.…”

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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Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators

Cited by 49 publications

References 95 publications

JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells

JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells

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

Drug Design Concepts for LSD1‐Selective Inhibitors

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