Development of a chemical probe against NUDT15

Nat Chem Biol. 2020 Oct;16(10):1120-1128. doi: 10.1038/s41589-020-0592-z.

Si Min Zhang ^# ¹, Matthieu Desroses ^# ¹, Anna Hagenkort ^# ¹, Nicholas C K Valerie ¹, Daniel Rehling ², Megan Carter ², Olov Wallner ¹, Tobias Koolmeister ¹, Adam Throup ¹, Ann-Sofie Jemth ¹, Ingrid Almlöf ¹, Olga Loseva ¹, Thomas Lundbäck ³, Hanna Axelsson ³, Shruti Regmi ³, Antonio Sarno ⁴, Andreas Krämer ⁵, Linda Pudelko ¹, Lars Bräutigam ¹, Azita Rasti ¹, Mona Göttmann ¹, Elisée Wiita ¹, Juliane Kutzner ⁶, Torsten Schaller ⁶, Christina Kalderén ¹, Armando Cázares-Körner ¹, Brent D G Page ¹ ⁷, Rosa Krimpenfort ⁸, Saeed Eshtad ⁸, Mikael Altun ⁹ ¹⁰, Sean G Rudd ¹, Stefan Knapp ⁵, Martin Scobie ¹, Evert J Homan ¹, Ulrika Warpman Berglund ¹, Pål Stenmark ² ¹¹, Thomas Helleday ¹² ¹³

Affiliations

1 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
2 Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
3 Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
5 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt, Germany.
6 Department of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.
7 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
8 Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
9 Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
10 Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
11 Department of Experimental Medical Science, Lund University, Lund, Sweden.
12 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. [email protected].
13 Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK. [email protected].
# Contributed equally.

PMID: 32690945 DOI: 10.1038/s41589-020-0592-z

Abstract

The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-139193

TH1760

NUDT15 Inhibitor

Others

Cancer

Name
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