Development of a chemical probe against NUDT15

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

doi:10.1038/s41589-020-0592-z

Development of a chemical probe against NUDT15

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1120-1128
Number of pages	9
Journal	Nature Chemical Biology
Volume	16
Issue number	10
Early online date	2020 Jul 20
DOIs	https://doi.org/10.1038/s41589-020-0592-z
Publication status	Published - 2020 Oct

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Biochemistry and Molecular Biology

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10.1038/s41589-020-0592-z

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Zhang, S. M., Desroses, M., Hagenkort, A., Valerie, N. C. K., Rehling, D., Carter, M., Wallner, O., Koolmeister, T., Throup, A., Jemth, A.-S., Almlöf, I., Loseva, O., Lundbäck, T., Axelsson, H., Regmi, S., Sarno, A., Krämer, A., Pudelko, L., Bräutigam, L., ... Helleday, T. (2020). Development of a chemical probe against NUDT15. Nature Chemical Biology, 16(10), 1120-1128. https://doi.org/10.1038/s41589-020-0592-z

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title = "Development of a chemical probe against NUDT15",

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.",

author = "Zhang, {Si Min} and Matthieu Desroses and Anna Hagenkort and Valerie, {Nicholas C K} and Daniel Rehling and Megan Carter and Olov Wallner and Tobias Koolmeister and Adam Throup and Ann-Sofie Jemth and Ingrid Alml{\"o}f and Olga Loseva and Thomas Lundb{\"a}ck and Hanna Axelsson and Shruti Regmi and Antonio Sarno and Andreas Kr{\"a}mer and Linda Pudelko and Lars Br{\"a}utigam and Azita Rasti and Mona G{\"o}ttmann and Elis{\'e}e Wiita and Juliane Kutzner and Torsten Schaller and Christina Kalder{\'e}n and Armando C{\'a}zares-K{\"o}rner and Page, {Brent D G} and Rosa Krimpenfort and Saeed Eshtad and Mikael Altun and Rudd, {Sean G} and Stefan Knapp and Martin Scobie and Homan, {Evert J} and Berglund, {Ulrika Warpman} and P{\aa}l Stenmark and Thomas Helleday",

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doi = "10.1038/s41589-020-0592-z",

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Zhang, SM, Desroses, M, Hagenkort, A, Valerie, NCK, Rehling, D, Carter, M, Wallner, O, Koolmeister, T, Throup, A, Jemth, A-S, Almlöf, I, Loseva, O, Lundbäck, T, Axelsson, H, Regmi, S, Sarno, A, Krämer, A, Pudelko, L, Bräutigam, L, Rasti, A, Göttmann, M, Wiita, E, Kutzner, J, Schaller, T, Kalderén, C, Cázares-Körner, A, Page, BDG, Krimpenfort, R, Eshtad, S, Altun, M, Rudd, SG, Knapp, S, Scobie, M, Homan, EJ, Berglund, UW, Stenmark, P & Helleday, T 2020, 'Development of a chemical probe against NUDT15', Nature Chemical Biology, vol. 16, no. 10, pp. 1120-1128. https://doi.org/10.1038/s41589-020-0592-z

TY - JOUR

T1 - Development of a chemical probe against NUDT15

AU - Zhang, Si Min

AU - Desroses, Matthieu

AU - Hagenkort, Anna

AU - Valerie, Nicholas C K

AU - Rehling, Daniel

AU - Carter, Megan

AU - Wallner, Olov

AU - Koolmeister, Tobias

AU - Throup, Adam

AU - Jemth, Ann-Sofie

AU - Almlöf, Ingrid

AU - Loseva, Olga

AU - Lundbäck, Thomas

AU - Axelsson, Hanna

AU - Regmi, Shruti

AU - Sarno, Antonio

AU - Krämer, Andreas

AU - Pudelko, Linda

AU - Bräutigam, Lars

AU - Rasti, Azita

AU - Göttmann, Mona

AU - Wiita, Elisée

AU - Kutzner, Juliane

AU - Schaller, Torsten

AU - Kalderén, Christina

AU - Cázares-Körner, Armando

AU - Page, Brent D G

AU - Krimpenfort, Rosa

AU - Eshtad, Saeed

AU - Altun, Mikael

AU - Rudd, Sean G

AU - Knapp, Stefan

AU - Scobie, Martin

AU - Homan, Evert J

AU - Berglund, Ulrika Warpman

AU - Stenmark, Pål

AU - Helleday, Thomas

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

U2 - 10.1038/s41589-020-0592-z

DO - 10.1038/s41589-020-0592-z

M3 - Article

C2 - 32690945

SN - 1552-4469

VL - 16

SP - 1120

EP - 1128

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 10

ER -

Development of a chemical probe against NUDT15

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