title: Small Molecule Microarray Based Discovery of PARP14 Inhibitors.
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.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive, Singapore, 117543, Singapore.
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.affiliation: Karolinska Institute, Department of Medical Biochemistry & Biophysics, Scheeles väg 2, 17177, Stockholm, Sweden.
authors.forename: Ann-Gerd
authors.initials: AG
authors.lastname: Thorsell
authors.affiliation: Karolinska Institute, Department of Medical Biochemistry & Biophysics, Scheeles väg 2, 17177, Stockholm, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.affiliation: Karolinska Institute, Department of Medical Biochemistry & Biophysics, Scheeles väg 2, 17177, Stockholm, Sweden.
authors.forename: Herwig
authors.initials: H
authors.lastname: Schüler
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive, Singapore, 117543, Singapore.
authors.forename: Shao Q
authors.initials: SQ
authors.lastname: Yao
mesh_terms: D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D046228:Microarray Analysis; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D054852:Small Molecule Libraries; C584083:PARP14 protein, human; D011065:Poly(ADP-ribose) Polymerases
keywords: PARP inhibitors; X-ray crystallography; click chemistry; high-throughput screening; microarrays