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

作者：Lee Seon Hyeong; Kim Nayeon; Kim Se Jin; Song Jaewhan; Gong Young Dae; Kim Soo Youl^*

来源：Journal of Cancer Research and Clinical Oncology, 2013, 139(8): 1279-1294.

DOI：10.1007/s00432-013-1433-1

• Quinoxaline derivative
• Transglutaminase 2
• Apoptosis
• Anti-cancer drug

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-kappa B activation through I-kappa B alpha 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. %26lt;br%26gt;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. %26lt;br%26gt;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-kappa B alpha 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. %26lt;br%26gt;GK13 showed a possibility that quinoxaline derivatives may be effective for anti-cancer activity via TGase 2 inhibition.

• 出版日期2013-8