Rational Design of Cell-Active Inhibitors of PARP10

Rory K. Morgan, Ilsa T. Kirby, Anke Vermehren-Schmaedick, Kelsie Rodriguez, Michael S. Cohen

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Poly-ADP-ribose polymerases (PARPs 1-16) have emerged as major regulators of diverse cellular processes. PARPs can be subclassified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While much is known about the cellular roles of PARPs that catalyze PARylation (e.g., PARP1), the function of PARPs that catalyze MARylation (e.g., PARP10) is substantially less understood. This is due in large part to the lack of small-molecule inhibitors that are selective for individual PARP family members that catalyze MARylation. Herein, we describe the rational design and synthesis of selective inhibitors of PARP10. Using structure-based design, we targeted a hydrophobic subpocket within the nicotinamide-binding site of PARP10. We synthesized a series of small molecules based on a 3,4-dihydroisoquinolin-1(2H)-one (dq, 1) scaffold that contain various substituents at the C-5 and C-6 positions designed to exploit this hydrophobic subpocket. We found a dq analogue (22) that contains a methyl group at the C-5 position and a substituted pyridine at the C-6 position that exhibits >10-fold selectivity for PARP10 over a large subset of other PARP family members. The results of this study will serve as a platform for future small-molecule probe development for PARP10 and other PARP family members that catalyze MARylation.

Original languageEnglish (US)
Pages (from-to)74-79
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume10
Issue number1
DOIs
StatePublished - Oct 1 2019

Keywords

  • ADP-ribosylation
  • MARylation
  • NAD
  • PARPs
  • PARylation
  • Rational design

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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