5NWH

Potent inhibitors of NUDT5 silence hormone signaling in breast cancer

5NWH の概要

• エントリーDOI: 10.2210/pdb5nwh/pdb
• 分子名称: ADP-sugar pyrophosphatase, 7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-piperazin-1-yl-purine-2,6-dione (3 entities in total)
• 機能のキーワード: nudix, inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49693.85

構造登録者

Carter, M.,Stenmark, P. (登録日: 2017-05-06, 公開日: 2018-04-04, 最終更新日: 2024-01-17)

主引用文献

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.,Almlof, I.,Font-Mateu, J.,Llona-Minguez, S.,Baranczewski, P.,Jeppsson, F.,Homan, E.,Almqvist, H.,Axelsson, H.,Regmi, S.,Gustavsson, A.L.,Lundback, T.,Scobie, M.,Stromberg, K.,Stenmark, P.,Beato, M.,Helleday, T.
Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells.
Nat Commun, 9:250-250, 2018

PubMed 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.

PubMed: 29343827
DOI: 10.1038/s41467-017-02293-7

実験手法

X-RAY DIFFRACTION (2.6 Å)