Synthesis and GGCT Inhibitory Activity of &lt;i&gt;N&lt;/i&gt;-Glutaryl-L-alanine Analogues

Hiromi,; Tokura, Y.; Hoshiya, Naoyuki; Uenishi, Jun’ichi

doi:10.1248/cpb.c16-00167

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…Our original GGCT inhibitor, GA, is designed by mimicking the substrate of glutamyl alanine and exerts GGCT inhibition activity on the homogenates of GGCT‐NIH‐3T3 cells, MCF7 cells (Figure ), HL‐60 cells, PC3 cells, or GGCT‐NHDF cells (data not shown), indicating that GA can inhibit not only recombinant GGCT, but also native GGCT, in cancer cells. However, no inhibitory activity was observed when living cells were treated, suggesting that GA was unable to sufficiently distribute inside living cells.…”

Section: Discussionmentioning

confidence: 99%

“…Glutaryl-l-Ala:T he compound was prepared as described previously. [15] Glutaryl-Lys(NBD) (gKFA):T he compound was prepared as described previously. [23] Simultaneous syntheses of Me-gKFA-Me and Me-gKFA:…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, we reported on novel inhibitors of GGCT enzymatic activity. N ‐Glutaryl‐ l ‐alanine (GA) and other compounds inhibit GGCT activity in vitro, which can be measured using multistep reaction methods or with the originally developed GGCT probe, LISA‐101 . However, a major obstacle of using these candidate compounds as anticancer agents is that they are unable to penetrate living cell membranes efficiently.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Prodrug of a γ‐Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer

et al. 2018

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γ-Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester-type cell-permeable prodrug, pro-GA, was developed based on the structure of N-glutaryl-l-alanine (GA), by structure optimization using temporary fluorophore-tagged prodrug candidates. The antiproliferative activity of pro-GA was demonstrated using GGCT-overexpressing NIH-3T3 cells and human cancer cells including MCF7, HL-60, and PC3 cells. By contrast, normal cells were not significantly affected by pro-GA treatment. Moreover, pro-GA administration exhibited anticancer effects in a xenograft model using immunocompromised mice inoculated with PC3 cells. These results indicate that the enzymatic activity of GGCT accelerates tumor growth and that GGCT inhibition is a promising therapeutic strategy for the treatment of GGCT-overexpressing tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Prodrug of a γ‐Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer

et al. 2018

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“…As the structure of an inhibitor of enzymatic activity often resembles the structure of the natural substrate of the enzyme, 18 compounds structurally similar to γ-glutamyl- l -amino acid were selected as candidates for GGCT inhibition. N -glutaryl- l -alanine (GA) was found to be the most potent inhibitor for GGCT by compound screening using the LISA-101 assay, a novel GGCT fluorogenic probe [ 33 , 34 ]. GA was an effective GGCT inhibitor in cell homogenates, but was unable to penetrate through the cell membranes.…”

Section: Development Of Ggct Inhibitorsmentioning

confidence: 99%

Mechanisms of Tumor Growth Inhibition by Depletion of γ-Glutamylcyclotransferase (GGCT): A Novel Molecular Target for Anticancer Therapy

Kageyama

Hiromi

Taniguchi

et al. 2018

IJMS

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γ-Glutamylcyclotransferase (GGCT), which is one of the major enzymes involved in glutathione metabolism, is upregulated in a wide range of cancers—glioma, breast, lung, esophageal, gastric, colorectal, urinary bladder, prostate, cervical, ovarian cancers and osteosarcoma—and promotes cancer progression; its depletion leads to the suppression of proliferation, invasion, and migration of cancer cells. It has been demonstrated that the suppression or inhibition of GGCT has an antitumor effect in cancer-bearing xenograft mice. Based on these observations, GGCT is now recognized as a promising therapeutic target in various cancers. This review summarizes recent advances on the mechanisms of the antitumor activity of GGCT inhibition.

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“…These results may be because the bulky side chain on the P 1 ' site prevented formation of the transition states in the enzymesubstrate complex. Based on the successful development of a GGCT probe, we designed a fluorescent-tagged inhibitor based on the structure of a known inhibitor, glutaryl-Ala [13,14]. As described earlier, GGCT strongly interacts with substrates at the α-carboxyl group of the P 1 ' site.…”

Section: Resultsmentioning

confidence: 99%

Design of fluorogenic probes and fluorescent‐tagged inhibitors for γ‐glutamyl cyclotransferase

Yoshiya

Hiromi

Tsuda

et al. 2017

Journal of Peptide Science

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A tumor-related protein, human chromosome 7 ORF 24 (C7orf24), is involved in regulation of the glutathione homeostasis cycle as a γ-glutamyl cyclotransferase (GGCT). The singular substrate preference of this enzyme had long hampered its chemical probe development. That is, substrate of GGCT is definitely 'γ-Glu-Xaa', where Xaa is an L-α-amino acid. Based on the structure of substrates and GGCT fluorogenic probes, LISA-4/101, we succesfully developed a fluorescent-tagged inhibitor, gKFA. These chemical tools will assist cancer-related researches in the future.

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Synthesis and GGCT Inhibitory Activity of <i>N</i>-Glutaryl-L-alanine Analogues

Cited by 7 publications

References 27 publications

A Novel Prodrug of a γ‐Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer

A Novel Prodrug of a γ‐Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer

Mechanisms of Tumor Growth Inhibition by Depletion of γ-Glutamylcyclotransferase (GGCT): A Novel Molecular Target for Anticancer Therapy

Design of fluorogenic probes and fluorescent‐tagged inhibitors for γ‐glutamyl cyclotransferase

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