title: Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11.
abstract: The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, California, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Yakushi
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Parlati
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mackinnon
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Perez
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
authors.forename: Yuyong
authors.identifier: 0000-0001-9591-6465
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Carter
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Colayco
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Magnuson
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Brock
authors.initials: B
authors.lastname: Brown
authors.affiliation: Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.affiliation: Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
authors.forename: Eigo
authors.initials: E
authors.lastname: Suyama
authors.affiliation: Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Thomas D Y
authors.identifier: 0000-0003-4856-6233
authors.initials: TDY
authors.lastname: Chung
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Palmer
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Pass
authors.affiliation: Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, California, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C109285:PSMD14 protein, human; D061988:Proteasome Inhibitors; D011804:Quinolines; D015534:Trans-Activators; C087618:8-mercaptoquinoline; D046988:Proteasome Endopeptidase Complex