Small Molecule Microarray Based Discovery of PARP14 Inhibitors

Bo Peng, Ann Gerd Thorsell, Tobias Karlberg, Herwig Schüler, Shao Q. Yao

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageEnglish
Pages (from-to)248-253
Number of pages6
JournalAngewandte Chemie - International Edition
Volume56
Issue number1
DOIs
StatePublished - 2 Jan 2017
Externally publishedYes

Keywords

  • click chemistry
  • high-throughput screening
  • microarrays
  • PARP inhibitors
  • X-ray crystallography

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