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

doi:10.1007/s00432-013-1433-1

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 journal › Article › peer-review

45 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 language	English
Pages (from-to)	1279-1294
Number of pages	16
Journal	Journal of cancer research and clinical oncology
Volume	139
Issue number	8
DOIs	https://doi.org/10.1007/s00432-013-1433-1
Publication status	Published - 2013 Aug

Bibliographical note

Funding Information:
Acknowledgments This work was supported by a research grant (NCC1110011-2) from the National Cancer Center in Korea to S.Y.K. and National R&D Program for Cancer Control (No. 1020050) in Korea to Y.D.G. We declare that none of the authors have a financial interest related to this work, and none of the authors have any financial support beyond the research grant mentioned above.

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00432-013-1433-1

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title = "Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor",

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.",

author = "Lee, {Seon Hyeong} and Nayeon Kim and Kim, {Se Jin} and Jaewhan Song and Gong, {Young Dae} and Kim, {Soo Youl}",

note = "Funding Information: Acknowledgments This work was supported by a research grant (NCC1110011-2) from the National Cancer Center in Korea to S.Y.K. and National R&D Program for Cancer Control (No. 1020050) in Korea to Y.D.G. We declare that none of the authors have a financial interest related to this work, and none of the authors have any financial support beyond the research grant mentioned above.",

year = "2013",

month = aug,

doi = "10.1007/s00432-013-1433-1",

language = "English",

volume = "139",

pages = "1279--1294",

journal = "Journal of cancer research and clinical oncology",

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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

N1 - Funding Information: Acknowledgments This work was supported by a research grant (NCC1110011-2) from the National Cancer Center in Korea to S.Y.K. and National R&D Program for Cancer Control (No. 1020050) in Korea to Y.D.G. We declare that none of the authors have a financial interest related to this work, and none of the authors have any financial support beyond the research grant mentioned above.

PY - 2013/8

Y1 - 2013/8

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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JO - Journal of cancer research and clinical oncology

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

Abstract

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