Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor

Seon Hyeong Lee, Nayeon Kim, Se Jin Kim, Jaewhan Song, Young Dae Gong, Soo Youl Kim

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Purpose: Transglutaminase 2 (TGase 2), a cross-linking enzyme, plays an important role in both pro-survival and anti-apoptosis during oncogenesis. For instance, TGase 2 induces NF-κB activation through I-κBα polymerization, which leads to the increase of pro-survival factors such as BCl-2. TGase 2 also suppresses apoptosis via depletion of caspase 3 and cathepsin D. Therefore, a specific TGase 2 inhibitor may become a very useful treatment for cancer showing high levels of TGase 2 expression. Methods: By small-molecule library screening, we managed to locate a competitive TGase 2 inhibiting quinoxaline compound (GK13) from 50 other quinoxaline derivatives. The 50 compounds that were screened represent a thousand structurally diverse, potentially pharmaceutical heterocyclic compound libraries, including benzopyrans, oxadiazoles, thiadiazoles, and quinoxalines. By measuring GI50, TGI, and LC50 using SRB assay, GK13 was selected. Results: In vitro enzyme kinetics using guinea pig liver TGase 2 showed that IC50 value was about 16.4 E-6 M. GK13 inhibits TGase 2-mediated I-κBα polymerization in a dose-dependent manner. LC50 of GK13 showed greater efficacy as 4.3E-4 M than LC50 of doxorubicin that showed efficacy as 3.87E-3 M in NCC72 composing 11 tissue origins and 72 cancer cell lines. Conclusion: GK13 showed a possibility that quinoxaline derivatives may be effective for anti-cancer activity via TGase 2 inhibition.

Original languageEnglish
Pages (from-to)1279-1294
Number of pages16
JournalJournal of cancer research and clinical oncology
Volume139
Issue number8
DOIs
Publication statusPublished - 2013 Aug 1

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Quinoxalines
Neoplasms
Polymerization
Thiadiazoles
Oxadiazoles
Apoptosis
Small Molecule Libraries
Benzopyrans
Heterocyclic Compounds
transglutaminase 2
Cathepsin D
Enzymes
Caspase 3
Doxorubicin
Inhibitory Concentration 50
Guinea Pigs
Carcinogenesis
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lee, Seon Hyeong ; Kim, Nayeon ; Kim, Se Jin ; Song, Jaewhan ; Gong, Young Dae ; Kim, Soo Youl. / Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor. In: Journal of cancer research and clinical oncology. 2013 ; Vol. 139, No. 8. pp. 1279-1294.
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abstract = "Purpose: Transglutaminase 2 (TGase 2), a cross-linking enzyme, plays an important role in both pro-survival and anti-apoptosis during oncogenesis. For instance, TGase 2 induces NF-κB activation through I-κBα polymerization, which leads to the increase of pro-survival factors such as BCl-2. TGase 2 also suppresses apoptosis via depletion of caspase 3 and cathepsin D. Therefore, a specific TGase 2 inhibitor may become a very useful treatment for cancer showing high levels of TGase 2 expression. Methods: By small-molecule library screening, we managed to locate a competitive TGase 2 inhibiting quinoxaline compound (GK13) from 50 other quinoxaline derivatives. The 50 compounds that were screened represent a thousand structurally diverse, potentially pharmaceutical heterocyclic compound libraries, including benzopyrans, oxadiazoles, thiadiazoles, and quinoxalines. By measuring GI50, TGI, and LC50 using SRB assay, GK13 was selected. Results: In vitro enzyme kinetics using guinea pig liver TGase 2 showed that IC50 value was about 16.4 E-6 M. GK13 inhibits TGase 2-mediated I-κBα polymerization in a dose-dependent manner. LC50 of GK13 showed greater efficacy as 4.3E-4 M than LC50 of doxorubicin that showed efficacy as 3.87E-3 M in NCC72 composing 11 tissue origins and 72 cancer cell lines. Conclusion: GK13 showed a possibility that quinoxaline derivatives may be effective for anti-cancer activity via TGase 2 inhibition.",
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Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor. / Lee, Seon Hyeong; Kim, Nayeon; Kim, Se Jin; Song, Jaewhan; Gong, Young Dae; Kim, Soo Youl.

In: Journal of cancer research and clinical oncology, Vol. 139, No. 8, 01.08.2013, p. 1279-1294.

Research output: Contribution to journalArticle

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T1 - Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor

AU - Lee, Seon Hyeong

AU - Kim, Nayeon

AU - Kim, Se Jin

AU - Song, Jaewhan

AU - Gong, Young Dae

AU - Kim, Soo Youl

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N2 - Purpose: Transglutaminase 2 (TGase 2), a cross-linking enzyme, plays an important role in both pro-survival and anti-apoptosis during oncogenesis. For instance, TGase 2 induces NF-κB activation through I-κBα polymerization, which leads to the increase of pro-survival factors such as BCl-2. TGase 2 also suppresses apoptosis via depletion of caspase 3 and cathepsin D. Therefore, a specific TGase 2 inhibitor may become a very useful treatment for cancer showing high levels of TGase 2 expression. Methods: By small-molecule library screening, we managed to locate a competitive TGase 2 inhibiting quinoxaline compound (GK13) from 50 other quinoxaline derivatives. The 50 compounds that were screened represent a thousand structurally diverse, potentially pharmaceutical heterocyclic compound libraries, including benzopyrans, oxadiazoles, thiadiazoles, and quinoxalines. By measuring GI50, TGI, and LC50 using SRB assay, GK13 was selected. Results: In vitro enzyme kinetics using guinea pig liver TGase 2 showed that IC50 value was about 16.4 E-6 M. GK13 inhibits TGase 2-mediated I-κBα polymerization in a dose-dependent manner. LC50 of GK13 showed greater efficacy as 4.3E-4 M than LC50 of doxorubicin that showed efficacy as 3.87E-3 M in NCC72 composing 11 tissue origins and 72 cancer cell lines. Conclusion: GK13 showed a possibility that quinoxaline derivatives may be effective for anti-cancer activity via TGase 2 inhibition.

AB - Purpose: Transglutaminase 2 (TGase 2), a cross-linking enzyme, plays an important role in both pro-survival and anti-apoptosis during oncogenesis. For instance, TGase 2 induces NF-κB activation through I-κBα polymerization, which leads to the increase of pro-survival factors such as BCl-2. TGase 2 also suppresses apoptosis via depletion of caspase 3 and cathepsin D. Therefore, a specific TGase 2 inhibitor may become a very useful treatment for cancer showing high levels of TGase 2 expression. Methods: By small-molecule library screening, we managed to locate a competitive TGase 2 inhibiting quinoxaline compound (GK13) from 50 other quinoxaline derivatives. The 50 compounds that were screened represent a thousand structurally diverse, potentially pharmaceutical heterocyclic compound libraries, including benzopyrans, oxadiazoles, thiadiazoles, and quinoxalines. By measuring GI50, TGI, and LC50 using SRB assay, GK13 was selected. Results: In vitro enzyme kinetics using guinea pig liver TGase 2 showed that IC50 value was about 16.4 E-6 M. GK13 inhibits TGase 2-mediated I-κBα polymerization in a dose-dependent manner. LC50 of GK13 showed greater efficacy as 4.3E-4 M than LC50 of doxorubicin that showed efficacy as 3.87E-3 M in NCC72 composing 11 tissue origins and 72 cancer cell lines. Conclusion: GK13 showed a possibility that quinoxaline derivatives may be effective for anti-cancer activity via TGase 2 inhibition.

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