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

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

  • Eur J Med Chem. 2016 Aug 8:118:316-27. doi: 10.1016/j.ejmech.2016.04.041.
Amit Nathubhai 1,  Teemu Haikarainen 2,  Penelope C Hayward 3,  Silvia Muñoz-Descalzo 4,  Andrew S Thompson 5,  Matthew D Lloyd 5,  Lari Lehtiö 2,  Michael D Threadgill 5
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK. Electronic address: [email protected].
  • 2 Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
  • 3 Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK.
  • 4 Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
  • 5 Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
PMID: 27163581 DOI: 10.1016/j.ejmech.2016.04.041
Abstract

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.

Keywords

2-Arylquinazolin-4-one; Hydrophobic cavity; PARP; Tankyrase; Wnt.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-23338
    TNKS-2 Inhibitor