title: Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity.
abstract: Inositol-requiring enzyme 1 (IRE-1) is a kinase/RNase ER stress sensor that is activated in response to excessive accumulation of unfolded proteins, hypoxic conditions, calcium imbalance, and other stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective effect and has been implicated in the progression of cancer via increased expression of the transcription factor XBP-1s. Here, we describe the synthesis and biological evaluation of novel chromenone-based covalent inhibitors of IRE-1. Preparation of a family of 8-formyltetrahydrochromeno[3,4-c]pyridines was achieved via a Duff formylation that is attended by an unusual cyclization reaction. Biological evaluation in vitro and in whole cells led to the identification of 30 as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression in wild type B cells and human mantle cell lymphoma cell lines.
authors.affiliation: Drug Discovery Department and ‡Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive MRC3E, Tampa, Florida 33612, United States.
authors.forename: Sujeewa
authors.initials: S
authors.lastname: Ranatunga
authors.forename: Chih-Hang Anthony
authors.initials: CH
authors.lastname: Tang
authors.forename: Chang Won
authors.initials: CW
authors.lastname: Kang
authors.forename: Crystina L
authors.initials: CL
authors.lastname: Kriss
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Kloppenburg
authors.forename: Chih-Chi Andrew
authors.initials: CC
authors.lastname: Hu
authors.forename: Juan R
authors.initials: JR
authors.lastname: Del Valle
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000138:chemical synthesis* / Q000494:pharmacology; D003500:Cyclization; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D002867:Chromones; D047428:Protein Kinase Inhibitors; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
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