Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity

DOI: 10.1021/jm401463y
PMID: 24116873

Authors: Mohit Narwal (University of Oulu; Abo Akademi University) , Jarkko Koivunen (University of Oulu) , Teemu Haikarainen (University of Oulu) , Ezeogo Obaji (University of Oulu) , Ongey Elvis Legala (University of Oulu) , Harikanth Venkannagari (University of Oulu) , Päivi Joensuu (University of Oulu) , Taina Pihlajaniemi (University of Oulu) , Lari Lehtio (University of Oulu)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56 (20)

State: Published (Approved)
Published: September 2013

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.

Journal Keywords: Crystallography; X-Ray; Drug; Flavones; HEK293; Heterocyclic; 3-Ring; Humans; Isoenzymes; L; Mice; Models; Molecular; Poly(ADP-ribose); Protein; Tertiary; Tankyrases; Wnt Signaling Pathway

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


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ID14-1, ID14-4, ID23-2 at ESRF

Added On: 04/10/2013 11:31

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)