1. Small Molecule Microarray Based Discovery of PARP14 Inhibitors
- Author
-
Bo Peng, Ann Gerd Thorsell, Herwig Schüler, Shao Q. Yao, and Tobias Karlberg
- Subjects
0301 basic medicine ,Poly ADP ribose polymerase ,High-throughput screening ,Poly(ADP-ribose) Polymerase Inhibitors ,010402 general chemistry ,01 natural sciences ,Catalysis ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,PARP1 ,Drug Discovery ,Transferase ,Humans ,chemistry.chemical_classification ,Nicotinamide ,010405 organic chemistry ,General Medicine ,General Chemistry ,Microarray Analysis ,Combinatorial chemistry ,Small molecule ,0104 chemical sciences ,High-Throughput Screening Assays ,030104 developmental biology ,Enzyme ,chemistry ,Biochemistry ,DNA microarray ,Poly(ADP-ribose) Polymerases - 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.
- Published
- 2016