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Development of a chemical probe against NUDT15

Zhang, Si Min ; Desroses, Matthieu ; Hagenkort, Anna ; Valerie, Nicholas C K ; Rehling, Daniel ; Carter, Megan ; Wallner, Olov ; Koolmeister, Tobias ; Throup, Adam and Jemth, Ann-Sofie , et al. (2020) In Nature Chemical Biology
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... (More)

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.

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@article{a17ef2f1-4926-4307-83b7-a01681382051,
  abstract     = {<p>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.</p>},
  author       = {Zhang, Si Min and Desroses, Matthieu and Hagenkort, Anna and Valerie, Nicholas C K and Rehling, Daniel and Carter, Megan and Wallner, Olov and Koolmeister, Tobias and Throup, Adam and Jemth, Ann-Sofie and Almlöf, Ingrid and Loseva, Olga and Lundbäck, Thomas and Axelsson, Hanna and Regmi, Shruti and Sarno, Antonio and Krämer, Andreas and Pudelko, Linda and Bräutigam, Lars and Rasti, Azita and Göttmann, Mona and Wiita, Elisée and Kutzner, Juliane and Schaller, Torsten and Kalderén, Christina and Cázares-Körner, Armando and Page, Brent D G and Krimpenfort, Rosa and Eshtad, Saeed and Altun, Mikael and Rudd, Sean G and Knapp, Stefan and Scobie, Martin and Homan, Evert J and Berglund, Ulrika Warpman and Stenmark, Pål and Helleday, Thomas},
  issn         = {1552-4469},
  language     = {eng},
  month        = {07},
  publisher    = {Nature Publishing Group},
  series       = {Nature Chemical Biology},
  title        = {Development of a chemical probe against NUDT15},
  url          = {http://dx.doi.org/10.1038/s41589-020-0592-z},
  doi          = {10.1038/s41589-020-0592-z},
  year         = {2020},
}