Small molecule inhibitors target the tissue transglutaminase and fibronectin interaction

Bakhtiyor Yakubov, Lan Chen, Alexey M. Belkin, Sheng Zhang, Bhadrani Chelladurai, Zhong Yin Zhang, Daniela Matei

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Tissue transglutaminase (TG2) mediates protein crosslinking through generation of ε-(γ-glutamyl) lysine isopeptide bonds and promotes cell adhesion through interaction with fibronectin (FN) and integrins. Cell adhesion to the peritoneal matrix regulated by TG2 facilitates ovarian cancer dissemination. Therefore, disruption of the TG2-FN complex by small molecules may inhibit cell adhesion and metastasis. A novel high throughput screening (HTS) assay based on AlphaLISA™ technology was developed to measure the formation of a complex between His-TG2 and the biotinylated FN fragment that binds TG2 and to discover small molecules that inhibit this protein-protein interaction. Several hits were identified from 10,000 compounds screened. The top candidates selected based on >70% inhibition of the TG2/FN complex formation were confirmed by using ELISA and bioassays measuring cell adhesion, migration, invasion, and proliferation. In conclusion, the AlphaLISA bead format assay measuring the TG2-FN interaction is robust and suitable for HTS of small molecules. One compound identified from the screen (TG53) potently inhibited ovarian cancer cell adhesion to FN, cell migration, and invasion and could be further developed as a potential inhibitor for ovarian cancer dissemination.

Original languageEnglish (US)
Article numbere89285
JournalPloS one
Volume9
Issue number2
DOIs
StatePublished - Feb 20 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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