Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Brent D G Page; Nicholas C K Valerie; Roni H G Wright; Olov Wallner; Rebecka Isaksson; Megan Carter; Sean G Rudd; Olga Loseva; Ann-Sofie Jemth; Ingrid Almlöf; Jofre Font-Mateu; Sabin Llona-Minguez; Pawel Baranczewski; Fredrik Jeppsson; Evert Homan; Helena Almqvist; Hanna Axelsson; Shruti Regmi; Anna-Lena Gustavsson; Thomas Lundbäck; Martin Scobie; Kia Strömberg; Pål Stenmark; Miguel Beato; Thomas Helleday

doi:10.1038/s41467-017-02293-7

Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Brent D G Page, Nicholas C K Valerie, Roni H G Wright, Olov Wallner, Rebecka Isaksson, Megan Carter, Sean G Rudd, Olga Loseva, Ann-Sofie Jemth, Ingrid Almlöf, Jofre Font-Mateu, Sabin Llona-Minguez, Pawel Baranczewski, Fredrik Jeppsson, Evert Homan, Helena Almqvist, Hanna Axelsson, Shruti Regmi, Anna-Lena Gustavsson, Thomas LundbäckMartin Scobie, Kia Strömberg, Pål Stenmark, Miguel Beato, Thomas Helleday

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

Abstract

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.

Original language	English
Article number	250
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02293-7
Publication status	Published - 2018 Jan 17
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Subject classification (UKÄ)

Cell and Molecular Biology
Cancer and Oncology

Free keywords

Adenosine Diphosphate Ribose/metabolism
Adenosine Triphosphate/metabolism
Breast Neoplasms/genetics
Cell Line, Tumor
Cell Nucleus/drug effects
Cell Proliferation/drug effects
Enzyme Inhibitors/chemistry
Female
HL-60 Cells
Humans
Molecular Structure
Progestins/metabolism
Pyrophosphatases/antagonists & inhibitors
RNA Interference
Signal Transduction/drug effects
Substrate Specificity

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10.1038/s41467-017-02293-7Licence: CC BY

Cite this

Page, B. D. G., Valerie, N. C. K., Wright, R. H. G., Wallner, O., Isaksson, R., Carter, M., Rudd, S. G., Loseva, O., Jemth, A.-S., Almlöf, I., Font-Mateu, J., Llona-Minguez, S., Baranczewski, P., Jeppsson, F., Homan, E., Almqvist, H., Axelsson, H., Regmi, S., Gustavsson, A.-L., ... Helleday, T. (2018). Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells. Nature Communications, 9(1), Article 250. https://doi.org/10.1038/s41467-017-02293-7

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title = "Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells",

abstract = "With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.",

keywords = "Adenosine Diphosphate Ribose/metabolism, Adenosine Triphosphate/metabolism, Breast Neoplasms/genetics, Cell Line, Tumor, Cell Nucleus/drug effects, Cell Proliferation/drug effects, Enzyme Inhibitors/chemistry, Female, HL-60 Cells, Humans, Molecular Structure, Progestins/metabolism, Pyrophosphatases/antagonists \& inhibitors, RNA Interference, Signal Transduction/drug effects, Substrate Specificity",

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year = "2018",

month = jan,

day = "17",

doi = "10.1038/s41467-017-02293-7",

language = "English",

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Page, BDG, Valerie, NCK, Wright, RHG, Wallner, O, Isaksson, R, Carter, M, Rudd, SG, Loseva, O, Jemth, A-S, Almlöf, I, Font-Mateu, J, Llona-Minguez, S, Baranczewski, P, Jeppsson, F, Homan, E, Almqvist, H, Axelsson, H, Regmi, S, Gustavsson, A-L, Lundbäck, T, Scobie, M, Strömberg, K, Stenmark, P, Beato, M & Helleday, T 2018, 'Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells', Nature Communications, vol. 9, no. 1, 250. https://doi.org/10.1038/s41467-017-02293-7

TY - JOUR

T1 - Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

AU - Page, Brent D G

AU - Valerie, Nicholas C K

AU - Wright, Roni H G

AU - Wallner, Olov

AU - Isaksson, Rebecka

AU - Carter, Megan

AU - Rudd, Sean G

AU - Loseva, Olga

AU - Jemth, Ann-Sofie

AU - Almlöf, Ingrid

AU - Font-Mateu, Jofre

AU - Llona-Minguez, Sabin

AU - Baranczewski, Pawel

AU - Jeppsson, Fredrik

AU - Homan, Evert

AU - Almqvist, Helena

AU - Axelsson, Hanna

AU - Regmi, Shruti

AU - Gustavsson, Anna-Lena

AU - Lundbäck, Thomas

AU - Scobie, Martin

AU - Strömberg, Kia

AU - Stenmark, Pål

AU - Beato, Miguel

AU - Helleday, Thomas

PY - 2018/1/17

Y1 - 2018/1/17

N2 - With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.

AB - With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.

KW - Adenosine Diphosphate Ribose/metabolism

KW - Adenosine Triphosphate/metabolism

KW - Breast Neoplasms/genetics

KW - Cell Line, Tumor

KW - Cell Nucleus/drug effects

KW - Cell Proliferation/drug effects

KW - Enzyme Inhibitors/chemistry

KW - Female

KW - HL-60 Cells

KW - Humans

KW - Molecular Structure

KW - Progestins/metabolism

KW - Pyrophosphatases/antagonists & inhibitors

KW - RNA Interference

KW - Signal Transduction/drug effects

KW - Substrate Specificity

UR - https://www.scopus.com/pages/publications/85041404218

U2 - 10.1038/s41467-017-02293-7

DO - 10.1038/s41467-017-02293-7

M3 - Article

C2 - 29343827

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 250

ER -

Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Abstract

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Subject classification (UKÄ)

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