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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Page, Brent D G; Valerie, Nicholas C K; Wright, Roni H G; Wallner, Olov; Isaksson, Rebecka; Carter, Megan; Rudd, Sean G; Loseva, Olga; Jemth, Ann-Sofie and Almlöf, Ingrid, et al. (2018) In Nature Communications 9(1).
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... (More)

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.

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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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Nature Communications
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9
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1
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Nature Publishing Group
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  • scopus:85041404218
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2041-1723
DOI
10.1038/s41467-017-02293-7
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English
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95e03731-d506-41db-b6c3-1392070d412c
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2019-04-30 07:50:29
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2019-10-08 03:50:02
@article{95e03731-d506-41db-b6c3-1392070d412c,
  abstract     = {<p>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.</p>},
  articleno    = {250},
  author       = {Page, Brent D G and Valerie, Nicholas C K and Wright, Roni H G and Wallner, Olov and Isaksson, Rebecka and Carter, Megan and Rudd, Sean G and Loseva, Olga and Jemth, Ann-Sofie and Almlöf, Ingrid and Font-Mateu, Jofre and Llona-Minguez, Sabin and Baranczewski, Pawel and Jeppsson, Fredrik and Homan, Evert and Almqvist, Helena and Axelsson, Hanna and Regmi, Shruti and Gustavsson, Anna-Lena and Lundbäck, Thomas and Scobie, Martin and Strömberg, Kia and Stenmark, Pål and Beato, Miguel and Helleday, Thomas},
  issn         = {2041-1723},
  keyword      = {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},
  language     = {eng},
  month        = {01},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells},
  url          = {http://dx.doi.org/10.1038/s41467-017-02293-7},
  volume       = {9},
  year         = {2018},
}