Selective inhibition of PARP10 using a chemical genetics strategy

Rory K. Morgan, Ian Carter-O'Connell, Michael S. Cohen

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The lack of inhibitors that are selective for individual poly-ADP-ribose polymerase (PARP) family members has limited our understanding of their roles in cells. Here, we describe a chemical genetics approach for generating selective inhibitors of an engineered variant of PARP10. We synthesized a series of C-7 substituted 3,4-dihydroisoquinolin-1(2H)-one (dq) analogues designed to selectively inhibit a mutant of PARP10 (LG-PARP10) that contains a unique pocket in its active site. A dq analogue containing a bromo at the C-7 position demonstrated a 10-fold selectivity for LG-PARP10 compared to its WT counterpart. This study provides a platform for the development of selective inhibitors of individual PARP family members that will be useful for decoding their cellular functions.

Original languageEnglish (US)
Pages (from-to)4770-4773
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number21
DOIs
StatePublished - Nov 1 2015

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Keywords

  • ADP-ribosylation
  • Chemical genetics
  • Click chemistry
  • PARPs

ASJC Scopus subject areas

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

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