Concepts and Molecular Aspects in the Polypharmacology of PARP-1 Inhibitors

ChemMedChem. 2016 Jun 20;11(12):1219-26. doi: 10.1002/cmdc.201500391. Epub 2015 Oct 1.


Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter-family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency.

Keywords: PARP-1 inhibitors; cancer; drug discovery; ischemia; polypharmacology.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Female
  • Humans
  • Molecular Dynamics Simulation
  • Ovarian Neoplasms / drug therapy
  • Phthalazines / chemistry
  • Phthalazines / metabolism
  • Phthalazines / therapeutic use
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Piperazines / therapeutic use
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
  • Poly(ADP-ribose) Polymerase Inhibitors / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Polypharmacology*
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism


  • Antineoplastic Agents
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly (ADP-Ribose) Polymerase-1
  • Protein Kinases
  • olaparib