Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases

Amit Nathubhai, Teemu Haikarainen, Penelope C Hayward, Silvia Muñoz-Descalzo, Andrew S Thompson, Matthew D Lloyd, Lari Lehtiö, Michael D Threadgill

Research output: Contribution to JournalArticlepeer-review


Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised. An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 4'-hydrophobic or electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NAD(+)-binding site contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.
Original languageEnglish
Pages (from-to)316-327
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Early online date20 Apr 2016
Publication statusPublished - 8 Aug 2016

Bibliographical note

Copyright © 2016 Elsevier Masson SAS. All rights reserved.


  • Animals
  • Cell Proliferation/drug effects
  • Enzyme Inhibitors/chemistry
  • Mice
  • Models, Molecular
  • Protein Conformation
  • Quinazolinones/chemistry
  • Structure-Activity Relationship
  • Tankyrases/antagonists & inhibitors
  • Wnt Signaling Pathway/drug effects


Dive into the research topics of 'Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases'. Together they form a unique fingerprint.

Cite this