University of Oulu

Sowa, S.T., Vela-Rodríguez, C., Galera-Prat, A. et al. A FRET-based high-throughput screening platform for the discovery of chemical probes targeting the scaffolding functions of human tankyrases. Sci Rep 10, 12357 (2020).

A FRET-based high-throughput screening platform for the discovery of chemical probes targeting the scaffolding functions of human tankyrases

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Author: Sowa, Sven T.1; Vela-Rodríguez, Carlos1; Galera-Prat, Albert1;
Organizations: 1Faculty for Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.6 MB)
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Language: English
Published: Springer Nature, 2020
Publish Date: 2020-12-02


Tankyrases catalyse poly-ADP-ribosylation of their binding partners and the modification serves as a signal for the subsequent proteasomal degradation of these proteins. Tankyrases thereby regulate the turnover of many proteins involved in multiple and diverse cellular processes, such as mitotic spindle formation, telomere homeostasis and Wnt/β-catenin signalling. In recent years, tankyrases have become attractive targets for the development of inhibitors as potential therapeutics against cancer and fibrosis. Further, it has become clear that tankyrases are not only enzymes, but also act as scaffolding proteins forming large cellular signalling complexes. While many potent and selective tankyrase inhibitors of the poly-ADP-ribosylation function exist, the inhibition of tankyrase scaffolding functions remains scarcely explored. In this work we present a robust, simple and cost-effective high-throughput screening platform based on FRET for the discovery of small molecule probes targeting the protein–protein interactions of tankyrases. Validatory screening with the platform led to the identification of two compounds with modest binding affinity to the tankyrase 2 ARC4 domain, demonstrating the applicability of this approach. The platform will facilitate identification of small molecules binding to tankyrase ARC or SAM domains and help to advance a structure-guided development of improved chemical probes targeting tankyrase oligomerization and substrate protein interactions.

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Series: Scientific reports
ISSN: 2045-2322
ISSN-E: 2045-2322
ISSN-L: 2045-2322
Volume: 10
Issue: 1
Article number: 12357
DOI: 10.1038/s41598-020-69229-y
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3111 Biomedicine
Funding: The research was 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)
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