1. Design, synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14
- Author
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Robert Lease, Jacob Holechek, Ryan Grant, Tobias Karlberg, Herwig Schüler, Dana Ferraris, Abby Keen, Caitlin McCadden, Ann-Gerd Thorsell, and Evan Callahan
- Subjects
0301 basic medicine ,Stereochemistry ,Poly ADP ribose polymerase ,Clinical Biochemistry ,Pharmaceutical Science ,Crystal structure ,Poly(ADP-ribose) Polymerase Inhibitors ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Structure-Activity Relationship ,PARP1 ,Proto-Oncogene Proteins ,Drug Discovery ,Transferase ,Potency ,Humans ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Amides ,0104 chemical sciences ,030104 developmental biology ,Design synthesis ,Drug Design ,Molecular Medicine ,Poly(ADP-ribose) Polymerases ,Selectivity ,Ethers - Abstract
A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets.
- Published
- 2018