Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries.

Journal Article (Journal Article)

Human tissue transglutaminase (TGM2) is a calcium-dependent crosslinking enzyme involved in the posttranslational modification of intra- and extracellular proteins and implicated in several neurodegenerative diseases. To find specific inhibitors to TGM2, two structurally diverse chemical libraries (LOPAC and Prestwick) were screened. We found that ZM39923, a Janus kinase inhibitor, and its metabolite ZM449829 were the most potent inhibitors with IC(50) of 10 and 5 nM, respectively. In addition, two other inhibitors, including tyrphostin 47 and vitamin K(3), were found to have an IC(50) in the micromolar range. These agents used in part a thiol-dependent mechanism to inhibit TGM2, consistent with the activation of TGM2 by reduction of an intramolecular disulfide bond. These inhibitors were tested in a polyglutamine-expressing Drosophila model of neurodegeneration and found to improve survival. The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases.

Full Text

Duke Authors

Cited Authors

  • Lai, T-S; Liu, Y; Tucker, T; Daniel, KR; Sane, DC; Toone, E; Burke, JR; Strittmatter, WJ; Greenberg, CS

Published Date

  • September 22, 2008

Published In

Volume / Issue

  • 15 / 9

Start / End Page

  • 969 - 978

PubMed ID

  • 18804034

Pubmed Central ID

  • PMC2637080

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2008.07.015


  • eng

Conference Location

  • United States