University of Oulu

J. Med. Chem. 2017, 60, 24, 10013–10025,

Discovery of a novel series of tankyrase inhibitors by a hybridization approach

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Author: Anumala, Upendra Rao1; Waaler, Jo2,3; Nkizinkiko, Yves4;
Organizations: 1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, 13125 Berlin, Germany
2Unit for Cell Signaling, Institute of Medical Microbiology, Oslo University Hospital, Gaustadalleen 34, 0372 Oslo, Norway
3Hybrid Technology Hub, Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0372 Oslo, Norway
4Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 5400, 90014 Oulu, Finland
5Department of Chemistry, Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia
6National University of Science and Technology MISiS, Leninsky Avenue 4, Moscow 119049, Russia
7Moscow Institute of Physics and Technology (State University), Institutskiy Lane 9, 141700 Dolgoprudny, Russia
8Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Strasse 2, 10178 Berlin, Germany
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.4 MB)
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Language: English
Published: American Chemical Society, 2017
Publish Date: 2021-02-26


A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC₅₀ values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.

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Series: Journal of medicinal chemistry
ISSN: 0022-2623
ISSN-E: 1520-4804
ISSN-L: 0022-2623
Volume: 60
Issue: 24
Pages: 10013 - 10025
DOI: 10.1021/acs.jmedchem.7b00883
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: Protein crystallography experiments were performed at the Diamond Light Source (Didcot, U.K.) on beamline I02 and at European Synchrotron Radiation Facility (ESRF, Grenoble, France) on beamline ID23-1. We are grateful to Local Contacts for providing assistance in using beamlines. The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under BioStruct-X (Grant Agreement No. 283570). The use of the facilities of the Biocenter Oulu Protein crystallography core facility, a member of Biocenter Finland and Instruct-FI, is gratefully acknowledged. The authors thank Bernd Rupp and Raed Al-Yamori (cheminformatics and software development) for the technical and scientific support in ChemAxon software deployment. The research was funded by Research Council of Norway “Extended biotarget validation studies for the specifc inhibitor of Wnt/β-catenin signaling OD270”, the Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, Biocenter Oulu and Academy of Finland (Grants 287063 and 294085 for L.L.), and the Russian Ministry of Education and Science (Grant 14.N08.11.0056 for A.G.M. and S.L.).
Academy of Finland Grant Number: 287063
Detailed Information: 287063 (Academy of Finland Funding decision)
294085 (Academy of Finland Funding decision)
Copyright information: © 2017 American Chemical Society. This is an open access article published under an ACS Author Choice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.