title: Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma.
abstract: Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematologic malignancies, including multiple myeloma (MM). Here, we report the identification of STF-083010, a novel small-molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after endoplasmic reticulum stress both in vitro and in vivo. Treatment with STF-083010 showed significant antimyeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells compared with other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBP1 axis is a promising target for anticancer therapy, especially in the context of MM.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Papandreou
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Denko
authors.forename: Michael
authors.initials: M
authors.lastname: Olson
authors.forename: Heleen
authors.initials: H
authors.lastname: Van Melckebeke
authors.forename: Sofie
authors.initials: S
authors.lastname: Lust
authors.forename: Arvin
authors.initials: A
authors.lastname: Tam
authors.forename: David E
authors.initials: DE
authors.lastname: Solow-Cordero
authors.forename: Donna M
authors.initials: DM
authors.lastname: Bouley
authors.forename: Fritz
authors.initials: F
authors.lastname: Offner
authors.forename: Maho
authors.initials: M
authors.lastname: Niwa
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002478:Cells, Cultured; D003603:Cytotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000008:administration & dosage; D013379:Substrate Specificity / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D003603:Cytotoxins; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C556690:STF 083010; D013449:Sulfonamides; D013876:Thiophenes; D000069286:Bortezomib; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases