Para-substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors

Teemu Haikarainen, Jarkko Koivunen, Mohit Narwal, Harikanth Venkannagari, Ezeogo Obaji, Päivi Joensuu, Taina Pihlajaniemi, Lari Lehtiö

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold′s phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain. TNKS for the inhibitors: A tankyrase inhibitor scaffold was identified, and a set of analogues were assayed for tankyrase inhibition. As a result, several highly potent and isoenzyme-selective inhibitors were discovered. Crystal structures of the compounds in complex with tankyrase 2 allowed us to rationalize inhibitor design using this and other similar scaffolds.

Original languageEnglish (US)
Pages (from-to)1978-1985
Number of pages8
JournalChemMedChem
Volume8
Issue number12
DOIs
StatePublished - Dec 2013
Externally publishedYes

Fingerprint

Tankyrases
Scaffolds
ADP Ribose Transferases
Diphtheria Toxin
Niacinamide
HEK293 Cells
X ray crystallography
X Ray Crystallography
Isoenzymes
Catalytic Domain
Substitution reactions
Crystal structure

Keywords

  • inhibitors
  • structural biology
  • structure-activity relationships
  • tankyrase
  • Wnt signaling

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Haikarainen, T., Koivunen, J., Narwal, M., Venkannagari, H., Obaji, E., Joensuu, P., ... Lehtiö, L. (2013). Para-substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors. ChemMedChem, 8(12), 1978-1985. https://doi.org/10.1002/cmdc.201300337

Para-substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors. / Haikarainen, Teemu; Koivunen, Jarkko; Narwal, Mohit; Venkannagari, Harikanth; Obaji, Ezeogo; Joensuu, Päivi; Pihlajaniemi, Taina; Lehtiö, Lari.

In: ChemMedChem, Vol. 8, No. 12, 12.2013, p. 1978-1985.

Research output: Contribution to journalArticle

Haikarainen, T, Koivunen, J, Narwal, M, Venkannagari, H, Obaji, E, Joensuu, P, Pihlajaniemi, T & Lehtiö, L 2013, 'Para-substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors', ChemMedChem, vol. 8, no. 12, pp. 1978-1985. https://doi.org/10.1002/cmdc.201300337
Haikarainen, Teemu ; Koivunen, Jarkko ; Narwal, Mohit ; Venkannagari, Harikanth ; Obaji, Ezeogo ; Joensuu, Päivi ; Pihlajaniemi, Taina ; Lehtiö, Lari. / Para-substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors. In: ChemMedChem. 2013 ; Vol. 8, No. 12. pp. 1978-1985.
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