title: Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  GK13 showed a possibility that quinoxaline derivatives may be effective for anti-cancer activity via TGase 2 inhibition.
authors.affiliation: Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
authors.forename: Seon-Hyeong
authors.initials: SH
authors.lastname: Lee
authors.forename: Nayeon
authors.initials: N
authors.lastname: Kim
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jaewhan
authors.initials: J
authors.lastname: Song
authors.forename: Young-Dae
authors.initials: YD
authors.lastname: Gong
authors.forename: Soo-Youl
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002469:Cell Separation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006801:Humans; D015151:Immunoblotting; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C583453:GK13 quinoxaline compound; D011810:Quinoxalines; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins