Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity

J Med Chem. 2013 Oct 24;56(20):7880-9. doi: 10.1021/jm401463y. Epub 2013 Oct 11.

Abstract

Tankyrases are ADP-ribosyltransferases that play key roles in various cellular pathways, including the regulation of cell proliferation, and thus, they are promising drug targets for the treatment of cancer. Flavones have been shown to inhibit tankyrases and we report here the discovery of more potent and selective flavone derivatives. Commercially available flavones with single substitutions were used for structure-activity relationship studies, and cocrystal structures of the 18 hit compounds were analyzed to explain their potency and selectivity. The most potent inhibitors were also tested in a cell-based assay, which demonstrated that they effectively antagonize Wnt signaling. To assess selectivity, they were further tested against a panel of homologous human ADP-ribosyltransferases. The most effective compound, 22 (MN-64), showed 6 nM potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling inhibition. This work forms a basis for rational development of flavones as tankyrase inhibitors and guides the development of other structurally related inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Discovery
  • Flavones / chemistry
  • Flavones / metabolism
  • Flavones / pharmacology*
  • HEK293 Cells
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • L Cells
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / chemistry
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Tankyrases / antagonists & inhibitors*
  • Tankyrases / chemistry
  • Tankyrases / metabolism
  • Wnt Signaling Pathway / drug effects

Substances

  • Flavones
  • Heterocyclic Compounds, 3-Ring
  • Isoenzymes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • XAV939
  • Poly(ADP-ribose) Polymerases
  • TNKS2 protein, human
  • Tankyrases
  • TNKS protein, human

Associated data

  • PDB/4BS4
  • PDB/4KZL
  • PDB/4KZQ
  • PDB/4KZU
  • PDB/4L09
  • PDB/4L0B
  • PDB/4L0I
  • PDB/4L0S
  • PDB/4L0T
  • PDB/4L0V
  • PDB/4L10
  • PDB/4L2F
  • PDB/4L2G
  • PDB/4L2K
  • PDB/4L31
  • PDB/4L32
  • PDB/4L33
  • PDB/4L34