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2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors

DOI: 10.1038/s41598-018-19872-3 DOI Help

Authors: Yves Nkizinkiko (University of Oulu) , Jenny Desantis (University of Perugia) , Jarkko Koivunen (University of Oulu) , Teemu Haikarainen (University of Oulu) , Sudarshan Murthy (University of Oulu) , Luca Sancineto (University of Perugia) , Serena Massari (University of Perugia) , Federica Ianni (University of Perugia) , Ezeogo Obaji (University of Oulu) , Maria I. Loza (University of Santiago de Compostela) , Taina Pihlajaniemi (University of Oulu) , Jose Brea (University of Santiago de Compostela) , Oriana Tabarrini (University of Perugia) , Lari Lehtiö (University of Oulu)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 8

State: Published (Approved)
Published: January 2018
Diamond Proposal Number(s): 14794

Open Access Open Access

Abstract: Tankyrases (TNKSs) are enzymes specialized in catalyzing poly-ADP-ribosylation of target proteins. Several studies have validated TNKSs as anti-cancer drug targets due to their regulatory role in Wnt/β-catenin pathway. Recently a lot of effort has been put into developing more potent and selective TNKS inhibitors and optimizing them towards anti-cancer agents. We noticed that some 2-phenylquinazolinones (2-PQs) reported as CDK9 inhibitors were similar to previously published TNKS inhibitors. In this study, we profiled this series of 2-PQs against TNKS and selected kinases that are involved in the Wnt/β-catenin pathway. We found that they were much more potent TNKS inhibitors than they were CDK9/kinase inhibitors. We evaluated the compound selectivity to tankyrases over the ARTD enzyme family and solved co-crystal structures of the compounds with TNKS2. Comparative structure-based studies of the catalytic domain of TNKS2 with selected CDK9 inhibitors and docking studies of the inhibitors with two kinases (CDK9 and Akt) revealed important structural features, which could explain the selectivity of the compounds towards either tankyrases or kinases. We also discovered a compound, which was able to inhibit tankyrases, CDK9 and Akt kinases with equal µM potency.

Journal Keywords: Small molecules; Structure-based drug design; X-ray crystallography

Diamond Keywords: Enzymes

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

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF

Added On: 29/03/2018 13:06


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)