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Design, synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14

DOI: 10.1016/j.bmcl.2018.04.056 DOI Help

Authors: Jacob Holechek (McDaniel College) , Robert Lease (McDaniel College) , Ann-gerd Thorsell (Karolinska Institutet) , Tobias Karlberg (Karolinska Institutet) , Caitlin Mccadden (McDaniel College) , Ryan Grant (McDaniel College) , Abby Keen (McDaniel College) , Evan Callahan (McDaniel College) , Herwig Schüler (Karolinska Institutet) , Dana Ferraris (McDaniel College)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 15806

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.

Journal Keywords: PARP; PARP10; PARP14; ARTD-8; Mono(ADP-ribosyl) transferase

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography