University of Oulu

Waaler, J., Leenders, R. G. G., Sowa, S. T., Alam Brinch, S., Lycke, M., Nieczypor, P., Aertssen, S., Murthy, S., Galera-Prat, A., Damen, E., Wegert, A., Nazaré, M., Lehtiö, L., & Krauss, S. (2020). Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor. Journal of Medicinal Chemistry, 63(13), 6834–6846.

Preclinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor

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Author: Waaler, Jo1,2; Leenders, Ruben G. G.3; Sowa, Sven T.4;
Organizations: 1Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317, Oslo, Norway
2Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway
3Mercachem BV, Kerkenbos 1013, 6546 BB Nijmegen, the Netherlands
4Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, PO Box 5400, 90014 Oulu, Finland
5Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin Buch, Robert-Roessle-Str. 10, 13125, Berlin, Germany
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 9.3 MB)
Persistent link:
Language: English
Published: American Chemical Society, 2020
Publish Date: 2021-06-08


Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC₃₀ inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.

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Series: Journal of medicinal chemistry
ISSN: 0022-2623
ISSN-E: 1520-4804
ISSN-L: 0022-2623
Volume: 63
Issue: 13
Pages: 6834 - 6846
DOI: 10.1021/acs.jmedchem.0c00208
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: J.W. and S.K. were supported by the Research Council of Norway (Grants 262613, 267639, and 296226), by South-Eastern Norway Regional Health Authority (Grants 16/00528-9, 15/00779-2, 2015012, and 2019090), and by the Norwegian Cancer Society (Grant 5803958). L.L., S.T.S., A.G.-P., and S.M. were supported by the Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, and Academy of Finland (Grants 287063, 294085, and 319299).
Academy of Finland Grant Number: 287063
Detailed Information: 287063 (Academy of Finland Funding decision)
294085 (Academy of Finland Funding decision)
319299 (Academy of Finland Funding decision)
Copyright information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see