1. Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease
- Author
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Robert K. Y. Cheng, Celia Dominguez, Osamu Ichihara, Douglas Macdonald, Ignacio Munoz-Sanjuan, Mark A. Brooks, Andreas Ebneth, Leticia Toledo-Sherman, Michael Prime, Ian Toogood-Johnson, Sayeh Erfan, John Wityak, Richard W Marston, Frederick Arthur Brookfield, Darshan Gunvant Vaidya, Stephen Martin Courtney, Peter Johnson, Anna Pedret-Dunn, Andreas Scheel, Dirk Winkler, Christopher John Yarnold, Sabine Schaertl, Ole A. Andersen, Shilpa Palan, Maria Beconi, Brunella Felicetti, Siw F. Johnsen, John J. Barker, Jordan J. Palfrey, and Ina Sternberger
- Subjects
Male ,Models, Molecular ,Cell Membrane Permeability ,Pyridines ,Tissue transglutaminase ,Lysine ,In Vitro Techniques ,Piperazines ,Mice ,Structure-Activity Relationship ,Huntington's disease ,GTP-Binding Proteins ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Protein Glutamine gamma Glutamyltransferase 2 ,chemistry.chemical_classification ,Acrylamides ,Sulfonamides ,Isopeptide bond ,Transglutaminases ,biology ,medicine.disease ,Molecular biology ,In vitro ,Rats ,Glutamine ,HEK293 Cells ,Huntington Disease ,Pyrimidines ,Enzyme ,Biochemistry ,chemistry ,Microsomes, Liver ,biology.protein ,Molecular Medicine ,Caco-2 Cells - 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.
- Published
- 2012
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