Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease.

Abstract

Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.

• Authors: Michael E Prime, Ole A Andersen, John J Barker, Mark A Brooks, Robert K Y Cheng, Ian Toogood-Johnson, Stephen M Courtney, Frederick A Brookfield, Christopher J Yarnold, Richard W Marston, Peter D Johnson, Siw F Johnsen, Jordan J Palfrey, Darshan Vaidya, Sayeh Erfan, Osamu Ichihara, Brunella Felicetti, Shilpa Palan, Anna Pedret-Dunn, Sabine Schaertl, Ina Sternberger, Andreas Ebneth, Andreas Scheel, Dirk Winkler, Leticia Toledo-Sherman, Maria Beconi, Douglas Macdonald, Ignacio Muñoz-Sanjuan, Celia Dominguez, John Wityak
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 3 Pg. 1021-46 (Feb 09 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22224594 (Publication Type: Journal Article)

Chemical References

• Acrylamides
• Piperazines
• Pyridines
• Pyrimidines
• Sulfonamides
• TGM2 protein, human
• Tgm2 protein, rat
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins

Topics

• Acrylamides (chemical synthesis, chemistry, pharmacology)
• Animals
• Caco-2 Cells
• Cell Membrane Permeability
• GTP-Binding Proteins (antagonists & inhibitors)
• HEK293 Cells
• Humans
• Huntington Disease (drug therapy)
• In Vitro Techniques
• Male
• Mice
• Microsomes, Liver (metabolism)
• Models, Molecular
• Piperazines (chemical synthesis, chemistry, pharmacology)
• Protein Glutamine gamma Glutamyltransferase 2
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Rats
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)
• Transglutaminases (antagonists & inhibitors)