Tankyrases as drug targets

FEBS J. 2013 Aug;280(15):3576-93. doi: 10.1111/febs.12320. Epub 2013 Jun 18.

Abstract

Tankyrase 1 and tankyrase 2 are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile α-motif multimerization domain and an ankyrin repeat protein-interaction domain. Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt-β-catenin signaling, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly(ADP-ribosyl)ation, and regulate protein interactions and stability. The proposed roles of tankyrases in disease-relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified. The selectivity and potency of these small molecules can be rationalized by how they fit within the NAD(+)-binding groove of the catalytic domain. Some molecules bind to the nicotinamide subsite, such as generic diphtheria toxin-like ADP-ribosyltransferase inhibitors, whereas others bind to a distinct adenosine subsite that diverges from other diphtheria toxin-like ADP-ribosyltransferases and confers specificity. A highly potent dual-site inhibitor is also available. Within the last few years, tankyrase inhibitors have proved to be useful chemical probes and potential lead compounds, especially for specific cancers.

Keywords: Wnt signalling; cancer; diphtheria toxin-like ADP-ribosyltransferase (ARTD); drug discovery; mitosis; poly(ADP-ribose) polymerase (PARP); tankyrase; telomere; vesicle trafficking.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Diphosphate Ribose / metabolism
  • Amino Acid Motifs
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Catalytic Domain
  • Humans
  • Mitosis
  • Models, Molecular
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational
  • Protein Transport
  • Tankyrases / antagonists & inhibitors*
  • Tankyrases / chemistry
  • Tankyrases / physiology
  • Telomere Homeostasis

Substances

  • Antineoplastic Agents
  • Adenosine Diphosphate Ribose
  • Tankyrases
  • Proteasome Endopeptidase Complex