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.

• Authors: Seon-Hyeong Lee, Nayeon Kim, Se-Jin Kim, Jaewhan Song, Young-Dae Gong, Soo-Youl Kim
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 139 Issue 8 Pg. 1279-94 (Aug 2013) ISSN: 1432-1335 [Electronic] Germany
• PMID: 23604466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• GK13 quinoxaline compound
• Quinoxalines
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Separation
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Flow Cytometry
• GTP-Binding Proteins (antagonists & inhibitors)
• Guinea Pigs
• Humans
• Immunoblotting
• Protein Glutamine gamma Glutamyltransferase 2
• Quinoxalines (chemical synthesis, chemistry, pharmacology)
• Transglutaminases (antagonists & inhibitors)