title: Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles.
abstract: Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity and have led to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R) stereoisomer.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA.
authors.forename: R Edward
authors.initials: RE
authors.lastname: Watts
authors.forename: Mathew
authors.initials: M
authors.lastname: Siegel
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
mesh_terms: D001665:Binding Sites; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D007555:Isoxazoles; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins