Article Metrics


Online attention

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

DOI: 10.1002/cmdc.201300337 DOI Help
PMID: 24130191 PMID Help

Authors: Teemu Haikarainen (University of Oulu) , Jarkko Koivunen (University of Oulu) , Mohit Narwal (Univ. of Oulu, Finland) , Harikanth Venkannagari (Univ. of Oulu, FInland) , Ezeogo Obaji (University of Oulu) , Päivi Joensuu (University of Oulu) , Taina Pihlajaniemi (University of Oulu) , Lari Lehtiö (University of Oulu)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem

State: Published (Approved)
Published: October 2013
Diamond Proposal Number(s): 8030

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.

Journal Keywords: Catalytic; Cell; Crystallography; X-Ray; Enzyme; HEK293; Humans; Hydrogen; Protein; Quinazolinones; Static; Structure-Activity; Tankyrases; Wnt Signaling Pathway

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Other Facilities: ESRF Lund

Added On: 17/09/2013 14:49

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)