title: Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries.
abstract: 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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. t.lai@duke.edu
authors.forename: Thung-S
authors.initials: TS
authors.lastname: Lai
authors.forename: Yusha
authors.initials: Y
authors.lastname: Liu
authors.forename: Tim
authors.initials: T
authors.lastname: Tucker
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Daniel
authors.forename: David C
authors.initials: DC
authors.lastname: Sane
authors.forename: Eric
authors.initials: E
authors.lastname: Toone
authors.forename: James R
authors.initials: JR
authors.lastname: Burke
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Strittmatter
authors.forename: Charles S
authors.initials: CS
authors.lastname: Greenberg
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D026122:Factor XIIIa / Q000037:antagonists & inhibitors / Q000378:metabolism; D019204:GTP-Binding Proteins; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D017827:Machado-Joseph Disease / Q000201:enzymology; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology; D017830:Octoxynol; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020032:Tyrphostins / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D009285:Naphthoquinones; C000717608:TGM2 protein, human; D020032:Tyrphostins; D006160:Guanosine Triphosphate; D017830:Octoxynol; D026122:Factor XIIIa; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002118:Calcium