title: Discovery of an Inhibitor of the Proteasome Subunit Rpn11.
abstract: The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn2+-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation. A fragment-based drug discovery (FBDD) approach was utilized to identify fragments with activity against Rpn11. Screening of a library of metal-binding pharmacophores (MBPs) revealed that 8-thioquinoline (8TQ, IC50value ∼2.5 μM) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQ yielded a small molecule compound (35, IC50value ∼400 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in culture.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Perez
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Francesco
authors.initials: F
authors.lastname: Parlati
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rouffet
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Yuyong
authors.initials: Y
authors.lastname: Ma
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mackinnon
authors.forename: Tsui-Fen
authors.initials: TF
authors.lastname: Chou
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Seth M
authors.identifier: 0000-0002-5233-2280
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: C109285:PSMD14 protein, human; D061988:Proteasome Inhibitors; D011804:Quinolines; D015534:Trans-Activators; D046988:Proteasome Endopeptidase Complex; D015032:Zinc