title: Acylideneoxoindoles: a new class of reversible inhibitors of human transglutaminase 2.
abstract: Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had K(i) values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Klöck
authors.forename: Xi
authors.initials: X
authors.lastname: Jin
authors.forename: Kihang
authors.initials: K
authors.lastname: Choi
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.forename: Peter B
authors.initials: PB
authors.lastname: Madrid
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.forename: Brian C
authors.initials: BC
authors.lastname: Raimundo
authors.forename: Paul
authors.initials: P
authors.lastname: Boardman
authors.forename: Guido
authors.initials: G
authors.lastname: Lanza
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins