title: Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2.
abstract: 3-halo-4,5-dihydroisoxazoles are attractive warheads for the selective inhibition of nucleophilic active sites in biological systems. A series of 3-bromo-4,5-dihydroisoxazole compounds were prepared and tested for their ability to irreversibly inhibit human transglutaminase 2 (TG2), an enzyme that plays an important role in the pathogenesis of diverse disorders including Celiac Sprue and certain types of cancers. Several compounds showed high specificity for human TG2 (k(inh)/K(I) > 2000 min(-1)M(-1)) but essentially no reactivity (k < 1 min(-1)M(-1)) toward physiological thiols such as glutathione. The pharmacokinetic and pharmacodynamic properties of a prototype dihydroisoxazole inhibitor, 1b, were evaluated; in mice the compound showed good oral bioavailability, short serum half-life and efficient TG2 inhibition in small intestinal tissue, and low toxicity. It also showed excellent synergism with N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU, carmustine) against refractory glioblastoma tumors in mice. A fluorescent dihydroisoxazole inhibitor 5 facilitated microscopic visualization of TG2 endocytosis from the extracellular surface of HCT-116 cells. Together, these findings demonstrate the promise of dihydroisoxazole compounds as probes for the biology of TG2 and its role in human disease.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA.
authors.forename: Kihang
authors.initials: K
authors.lastname: Choi
authors.forename: Matthew
authors.initials: M
authors.lastname: Siegel
authors.forename: Justin L
authors.initials: JL
authors.lastname: Piper
authors.forename: Liya
authors.initials: L
authors.lastname: Yuan
authors.forename: Eun
authors.initials: E
authors.lastname: Cho
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.forename: Bishr
authors.initials: B
authors.lastname: Omary
authors.forename: Keith M
authors.initials: KM
authors.lastname: Rich
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D018613:Microscopy, Confocal; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002330:Carmustine