The kinase polypharmacology landscape of clinical PARP inhibitors

Sci Rep. 2020 Feb 17;10(1):2585. doi: 10.1038/s41598-020-59074-4.

Abstract

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / chemistry*
  • Binding Sites
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • HEK293 Cells
  • Humans
  • Indazoles / administration & dosage
  • Indazoles / adverse effects
  • Indazoles / chemistry*
  • Indoles / administration & dosage
  • Indoles / adverse effects
  • Indoles / chemistry*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Phthalazines / administration & dosage
  • Phthalazines / adverse effects
  • Phthalazines / chemistry*
  • Piperazines / administration & dosage
  • Piperazines / adverse effects
  • Piperazines / chemistry*
  • Piperidines / administration & dosage
  • Piperidines / adverse effects
  • Piperidines / chemistry*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage
  • Poly(ADP-ribose) Polymerase Inhibitors / adverse effects
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
  • Polypharmacology
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Substrate Specificity

Substances

  • Antineoplastic Agents
  • Indazoles
  • Indoles
  • Isoenzymes
  • Phthalazines
  • Piperazines
  • Piperidines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins
  • rucaparib
  • talazoparib
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • PIM3 protein, human
  • Protein-Serine-Threonine Kinases
  • Cyclin-Dependent Kinases
  • PCTAIRE-1 protein kinase
  • niraparib
  • olaparib