5lyh
From Proteopedia
Human PARP14 (ARTD8), catalytic fragment in complex with inhibitor H10
Structural highlights
FunctionPAR14_HUMAN Enhances STAT6-dependent transcription (By similarity). Has ADP-ribosyltransferase activity. Publication Abstract from PubMedPoly(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. Small Molecule Microarray Based Discovery of PARP14 Inhibitors.,Peng B, Thorsell AG, Karlberg T, Schuler H, Yao SQ Angew Chem Int Ed Engl. 2016 Dec 5. doi: 10.1002/anie.201609655. PMID:27918638[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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