A potent and selective inhibitor for the UBLCP1 proteasome phosphatase

Yantao He, Xing Guo, Zhi Hong Yu, Li Wu, Andrea M. Gunawan, Yan Zhang, Jack E. Dixon, Zhong Yin Zhang

Research output: Contribution to journalArticle

8 Scopus citations

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 IC<inf>50</inf> of 1.0 μM 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.

Original languageEnglish (US)
Pages (from-to)2798-2809
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number12
DOIs
StatePublished - May 29 2015

Keywords

  • Fragment-based drug discovery
  • Inhibitor development
  • Protein phosphatase
  • UBLCP1

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'A potent and selective inhibitor for the UBLCP1 proteasome phosphatase'. Together they form a unique fingerprint.

  • Cite this