University of Oulu

Nkizinkiko, Y., Desantis, J., Koivunen, J., Haikarainen, T., Murthy, S., Sancineto, L., Massari, S., Ianni, F., Obaji, E., Loza, M., Pihlajaniemi, T., Brea, J., Tabarrini, O., Lehtiö, L. (2018) 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors. Scientific Reports, 8, 1680. doi:10.1038/s41598-018-19872-3

2-phenylquinazolinones as dual-activity tankyrase-kinase inhibitors

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Author: Nkizinkiko, Yves1; Desantis, Jenny2; Koivunen, Jarkko1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
2Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, Italy
3Present address: Center of molecular and macromolecules studies, Polish academy of science, Sienkiewicza 112, 90-363, Lodz, Poland
4Biofarma research group, Centro de Investigación CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.8 MB)
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Language: English
Published: Springer Nature, 2018
Publish Date: 2018-03-14


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.

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Series: Scientific reports
ISSN: 2045-2322
ISSN-E: 2045-2322
ISSN-L: 2045-2322
Volume: 8
Article number: 1680
DOI: 10.1038/s41598-018-19872-3
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was funded by Biocenter Oulu, the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation, Magnus Ehrnrooth Foundation and the Academy of Finland (grant no. 287063 and 294085 to LL, 266922 to TH, 294617 to JK and 284605 to TP). The research leading to these results has also received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under BioStruct-X (grant agreement N°283570). The use of the facilities and expertise of the Biocenter Oulu core facility, a member of Biocenter Finland and Instruct-FI, is gratefully acknowledged. We also thank the COST action CA15135 (Multi-Target Paradigm for Innovative Ligand Identification in the Drug Discovery Process, MuTaLig) for support.
EU Grant Number: (283570) BIOSTRUCT-X - Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities
Academy of Finland Grant Number: 287063
Detailed Information: 287063 (Academy of Finland Funding decision)
294085 (Academy of Finland Funding decision)
266922 (Academy of Finland Funding decision)
294617 (Academy of Finland Funding decision)
284605 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit .