Small Molecule Microarray Based Discovery of PARP14 Inhibitors

Angew Chem Int Ed Engl. 2017 Jan 2;56(1):248-253. doi: 10.1002/anie.201609655. Epub 2016 Dec 5.

Abstract

Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure-activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.

Keywords: PARP inhibitors; X-ray crystallography; click chemistry; high-throughput screening; microarrays.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery*
  • High-Throughput Screening Assays
  • Humans
  • Microarray Analysis
  • Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Small Molecule Libraries
  • PARP14 protein, human
  • Poly(ADP-ribose) Polymerases