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

Bioorganic & Medicinal Chemistry Letters
Jacob HolechekDana Ferraris

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.

Citations

Sep 8, 2020·Future Medicinal Chemistry·Amanda L TauberStephanie S Schweiker
Mar 21, 2019·Frontiers in Pharmacology·Wei QinHui-Ling Cao
Jan 21, 2021·Future Medicinal Chemistry·Amanda L TauberStephan M Levonis
Feb 9, 2021·Expert Opinion on Therapeutic Patents·Uday Kiran VelagapudiTanaji T Talele
Apr 11, 2021·Chembiochem : a European Journal of Chemical Biology·Tim J WigleKevin W Kuntz
Mar 12, 2019·Journal of the American Chemical Society·Lik Hang YuenRaphael M Franzini
Jan 19, 2019·ACS Medicinal Chemistry Letters·Rory K MorganMichael S Cohen
Jul 30, 2021·The FEBS Journal·Bernhard LüscherMathias Ziegler

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