Small Molecule Inhibitors Target the Tissue Transglutaminase and Fibronectin Interaction

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Mar 4

PMID 24586660

Citations 22

Authors

Bakhtiyor Yakubov

Lan Chen

Alexey M Belkin

Sheng Zhang

Bhadrani Chelladurai

Zhong-Yin Zhang

Daniela Matei

Affiliations

Soon will be listed here.

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.

Citing Articles

In silico studies of the open form of human tissue transglutaminase.

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The effect of TG2-inhibitory monoclonal antibody zampilimab on tissue fibrosis in human in vitro and primate in vivo models of chronic kidney disease.

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Guerrero-Barbera G, Burday N, Costell M Front Cell Dev Biol. 2024; 12:1363004.

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Elevated tissue transglutaminase levels in aqueous humor of congenital cataractous eyes with long axial length.

Yang T, Zhou X, Li H, Fan F, Yang J, Lin X Heliyon. 2023; 9(8):e18709.

PMID: 37576301 PMC: 10412761. DOI: 10.1016/j.heliyon.2023.e18709.

Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2).

Valdivia A, Vagadia P, Guo G, OBrien E, Matei D, Schiltz G J Med Chem. 2023; 66(14):9445-9465.

PMID: 37449845 PMC: 10388319. DOI: 10.1021/acs.jmedchem.2c01859.

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