title: A potent and selective inhibitor for the UBLCP1 proteasome phosphatase.
abstract: The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) has been implicated as a negative regulator of the proteasome, a key mediator in the ubiquitin-dependent protein degradation. Small molecule inhibitors that block UBLCP1 activity would be valuable as research tools and potential therapeutics for human diseases caused by the cellular accumulation of misfold/damaged proteins. We report a salicylic acid fragment-based library approach aimed at targeting both the phosphatase active site and its adjacent binding pocket for enhanced affinity and selectivity. Screening of the focused libraries led to the identification of the first potent and selective UBLCP1 inhibitor 13. Compound 13 exhibits an IC50 of 1.0μM for UBLCP1 and greater than 5-fold selectivity against a large panel of protein phosphatases from several distinct families. Importantly, the inhibitor possesses efficacious cellular activity and is capable of inhibiting UBLCP1 function in cells, which in turn up-regulates nuclear proteasome activity. These studies set the groundwork for further developing compound 13 into chemical probes or potential therapeutic agents targeting the UBLCP1 phosphatase.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pharmacology, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gunawan
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300, Austin, TX 78712, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA. Electronic address: zyzhang@iu.edu.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020156:Salicylic Acid / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D010749:Phosphoprotein Phosphatases; C502029:UBLCP1 protein, human; D020156:Salicylic Acid
keywords: Fragment-based drug discovery; Inhibitor development; Protein phosphatase; UBLCP1