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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3,8-trimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
slight inhibition
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(4-methylpiperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(4-methylpiperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(methylamino)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(morpholin-4-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
lead compound, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. Inhibitor-enzyme complex structure analysis, overview. TH5427 has no effect on NUDT9-mediated hydrolysis of ADPR, indicating discrimination amongst ADP-ribose hydrolases
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(piperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(propan-2-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-propyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(4-ethylpiperazin-1-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(4-hexylpiperazin-1-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(diethylamino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(dimethylamino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(ethylsulfanyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-methoxy-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-[(2-hydroxyethyl)amino]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
-
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-[4-(2-hydroxyethyl)piperidin-1-yl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
-
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-[di(prop-2-en-1-yl)amino]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-(4-butylpiperazin-1-yl)-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
-
8-(azepan-1-yl)-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-(cyclohexylsulfanyl)-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-benzyl-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-bromo-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-chloro-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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N(G)-nitro-L-arginine methyl ester
-
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tert-butyl 4-(7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylate
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additional information
small molecule screening, and identification of potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Inhibitors chelerythrine (a PKC inhibitor), LY294002 (a PI3K inhibitor), as well as 4-coumaric acid and flavone have no direct inhibitory effect on NUDT5 activity in the enzyme-coupled malachite green assay
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malfunction
enzyme inhibition by inhibitor TH5427 blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. Following depletion with NUDT5 siRNAs prior to cell lysis, ADPR hydrolysis is markedly attenuated compared to non-targeting siRNA controls. This can be rescued by the addition of recombinant NUDT5 protein. siRNA-mediated knockdown of NUDT5 alone does not appreciably induce DNA damage signaling in U2-OS cells, as measured by multiple DNA damage markers
additional information
NUDIX5 homodimer exists in equilibrium between the dominant ADPR hydrolysing conformation and a minor ATP synthesising conformation, in which the relative orientation of the monomer flips yielding more open active sites that can accommodate the presence of diphosphate required for ATP synthesis
metabolism
chromatin remodelling measured by histones H1 and H2A displacement at later stages after PAR accumulation and degradation, is dependent on PARP1, PARG, and NUDIX5
metabolism
involvement of NUDT5 in ADP-ribose metabolism, overview
physiological function
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ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling
physiological function
enzyme NUDT5 is implicated in ADP-ribose and 8-oxo-guanine metabolism and is a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. NUDT5 catalyzes the breakdown of ADPR to ribose-5-phosphate (R5P) and adenosine 5'-monophosphate (AMP), which permits recovery of NAD+ pools after DNA damage and poly(ADPR) polymerase (PARP) activation. In addition, NUDT5 is responsible for the production of PAR-mediated nuclear ATP and, thus, subsequent ATP-dependent chromatin remodeling and gene regulation following progestin or estrogen stimulation in breast cancer cells. NUDT5 activity is critical to elicit nuclear ATP production following hormone stimulation
physiological function
in response to hormones, i.e. synthetic promegestone (R5020 or 17alpha,21-dimethyl-19-norpregna-4,9-diene-3,20-dione), a nuclear ATP synthesis mechanism is activated that utilizes ADP-ribose and diphosphate as substrates. Enzyme NUDIX5 utilizes an increase in ADP-D-ribose and diphosphate to generate ATP. ATP produced in the nucleus is used for stable displacement of H1 and H2A/H2B opening the chromatin for access of transcriptional regulators leading to gene activation/repression and ultimately to cell proliferation. NUDIX5 interacts with both poly-ADP-ribose glycohydrolase (PARG) and poly-ADP-ribose (PAR) by co-immunoprecipitation following hormone treatment
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Yu, H.N.; Song, E.K.; Yoo, S.M.; Lee, Y.R.; Han, M.K.; Yim, C.Y.; Kwak, J.Y.; Kim, J.S.
Activation of NUDT5, an ADP-ribose pyrophosphatase, by nitric oxide-mediated ADP-ribosylation
Biochem. Biophys. Res. Commun.
354
764-768
2007
Homo sapiens
brenda
Wright, R.H.; Lioutas, A.; Le Dily, F.; Soronellas, D.; Pohl, A.; Bonet, J.; Nacht, A.S.; Samino, S.; Font-Mateu, J.; Vicent, G.P.; Wierer, M.; Trabado, M.A.; Schelhorn, C.; Carolis, C.; Macias, M.J.; Yanes, O.; Oliva, B.; Beato, M.
ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling
Science
352
1221-1225
2016
Homo sapiens
brenda
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.; Almloef, I.; Font-Mateu, J.; Llona-Minguez, S.; Baranczewski, P.; Jeppsson, F.; Homan, E.; Almqvist, H.; Axelsson, H.; Regmi, S.; Gustavsson, A.L.; Lundbaeck, T.; Scobie, M.; Stroemberg, K.; Stenamrk, P.; Beato, M.; Helleday, T.
Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
Nat. Commun.
9
250
2018
Homo sapiens (Q9UKK9)
brenda
Wright, R.; Fernandez-Fuentes, N.; Oliva, B.; Beato, M.
Insight into the machinery that oils chromatin dynamics
Nucleus
7
532-539
2016
Homo sapiens (Q9UKK9)
brenda