Discovery and Structure鈥揂ctivity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington鈥檚 Disease
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- 作者：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 Mu帽oz-Sanjuan ; Celia Dominguez ; John Wityak
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：February 9, 2012
- 年：2012
- 卷：55
- 期：3
- 页码：1021-1046
- 全文大小：904K
- 年卷期：v.55,no.3(February 9, 2012)
- ISSN：1520-4804
文摘
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鈥檚 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.