University of Oulu

Leenders, R. G. G., Brinch, S. A., Sowa, S. T., Amundsen-Isaksen, E., Galera-Prat, A., Murthy, S., Aertssen, S., Smits, J. N., Nieczypor, P., Damen, E., Wegert, A., Nazaré, M., Lehtiö, L., Waaler, J., & Krauss, S. (2021). Development of a 1,2,4-triazole-based lead tankyrase inhibitor: Part ii. Journal of Medicinal Chemistry, 64(24), 17936–17949.

Development of a 1,2,4-triazole-based lead tankyrase inhibitor : part II

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Author: Krauss, Stefan1,2; Leenders, Ruben G. G.3; Brinch, Shoshy Alam1,2;
Organizations: 1Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
2Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway
3Symeres, 6546 BB Nijmegen, The Netherlands
4Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
5Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
6Medicinal Chemistry, Leibniz- Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.2 MB)
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Language: English
Published: American Chemical Society, 2021
Publish Date: 2021-12-17


Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure–activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC₅₉ inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.

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Series: Journal of medicinal chemistry
ISSN: 0022-2623
ISSN-E: 1520-4804
ISSN-L: 0022-2623
Volume: 64
Issue: 24
Pages: 17936 - 17949
DOI: 10.1021/acs.jmedchem.1c01264
Type of Publication: A1 Journal article – refereed
Field of Science: 116 Chemical sciences
1182 Biochemistry, cell and molecular biology
Funding: S.K. was supported by the Research Council of Norway (grant nos. 262613 and 267639) and by South-Eastern Norway Regional Health Authority (grant nos. 16/00528-9, 15/00779-2, and 2015012). S.A.B. and J.W. were supported by the South-Eastern Norway Regional Health Authority (grant nos. 2019090 and 2021035). 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 (grant nos. 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: © 2021 The Authors. Published by American Chemical Society. This is an open access article published under Creatice Commons Attribution 4.0 International license (CC BY 4.0).