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

Publication ,  Journal Article
Lai, T-S; Liu, Y; Tucker, T; Daniel, KR; Sane, DC; Toone, E; Burke, JR; Strittmatter, WJ; Greenberg, CS
Published in: Chem Biol
September 22, 2008

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.

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Published In

Chem Biol

DOI

ISSN

1074-5521

Publication Date

September 22, 2008

Volume

15

Issue

9

Start / End Page

969 / 978

Location

United States

Related Subject Headings

  • Tyrphostins
  • Transglutaminases
  • Protein Glutamine gamma Glutamyltransferase 2
  • Organic Chemistry
  • Octoxynol
  • Naphthoquinones
  • Molecular Structure
  • Machado-Joseph Disease
  • Humans
  • Guanosine Triphosphate
 

Citation

APA
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Lai, T.-S., Liu, Y., Tucker, T., Daniel, K. R., Sane, D. C., Toone, E., … Greenberg, C. S. (2008). Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries. Chem Biol, 15(9), 969–978. https://doi.org/10.1016/j.chembiol.2008.07.015
Lai, Thung-S, Yusha Liu, Tim Tucker, Kurt R. Daniel, David C. Sane, Eric Toone, James R. Burke, Warren J. Strittmatter, and Charles S. Greenberg. “Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries.Chem Biol 15, no. 9 (September 22, 2008): 969–78. https://doi.org/10.1016/j.chembiol.2008.07.015.
Lai T-S, Liu Y, Tucker T, Daniel KR, Sane DC, Toone E, et al. Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries. Chem Biol. 2008 Sep 22;15(9):969–78.
Lai, Thung-S., et al. “Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries.Chem Biol, vol. 15, no. 9, Sept. 2008, pp. 969–78. Pubmed, doi:10.1016/j.chembiol.2008.07.015.
Lai T-S, Liu Y, Tucker T, Daniel KR, Sane DC, Toone E, Burke JR, Strittmatter WJ, Greenberg CS. Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries. Chem Biol. 2008 Sep 22;15(9):969–978.
Journal cover image

Published In

Chem Biol

DOI

ISSN

1074-5521

Publication Date

September 22, 2008

Volume

15

Issue

9

Start / End Page

969 / 978

Location

United States

Related Subject Headings

  • Tyrphostins
  • Transglutaminases
  • Protein Glutamine gamma Glutamyltransferase 2
  • Organic Chemistry
  • Octoxynol
  • Naphthoquinones
  • Molecular Structure
  • Machado-Joseph Disease
  • Humans
  • Guanosine Triphosphate