Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14

Bioorg Med Chem Lett. 2017 Jul 1;27(13):2907-2911. doi: 10.1016/j.bmcl.2017.04.089. Epub 2017 Apr 29.

Abstract

A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC50=160nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Structure-Activity Relationship

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP14 protein, human
  • Poly(ADP-ribose) Polymerases