Design, synthesis and evaluation of potential inhibitors for poly(ADP-ribose) polymerase members 1 and 14

Future Med Chem. 2020 Dec;12(24):2179-2190. doi: 10.4155/fmc-2020-0218. Epub 2020 Nov 23.

Abstract

Poly(ADP-ribose) polymerase (PARP) members PARP1 and PARP14 belong to an 18-member superfamily of post-translational modifying enzymes. A library of 9 novel non-NAD analog amine compounds was designed, synthesized and evaluated for inhibitory activity against PARP1 and PARP14. Both in silico studies and in vitro assays identified compound 2 as a potential PARP1 inhibitor, inhibiting activity by 93 ± 2% (PARP14 inhibition: 0 ± 6%), and 7 as a potential PARP14 inhibitor, inhibiting activity by 91 ± 2% (PARP1 inhibition: 18 ± 4%), at 10-μm concentration. Key in silico interactions with TYR907 in PARP1 and TYR1620 and TYR1646 in PARP14 have been identified. Compound 2 and compound 7 have been identified as potential leads for the development of selective PARP inhibitors.

Keywords: PARP inhibitors; PARP1; PARP14; molecular docking; reductive amination.

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-1 / antagonists & inhibitors*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1