Inhibition of the human deacylase Sirtuin 5 by the indole GW5074

Suenkel, Benjamin; Fischer, F.; Steegborn, Clemens

doi:10.1016/j.bmcl.2012.10.136

Cited by 47 publications

(35 citation statements)

References 33 publications

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“…However, to date, few specific pharmacological inhibitors have been reported yet for human SIRT5. Suenkel et al (2013) recently reported that the indole GW5074 is a potent inhibitor for SIRT5's desuccinylation activity, identifying a first pharmacological scaffold for development into SIRT5-specific inhibitor [26]. Previous studies also reported that GW5074 could inhibits SIRT2 deacetylation activity with a potency comparable to SIRT (reduction to less than 60% activity with 12.5 μM GW5074) [27,28].…”

Section: Discussionmentioning

confidence: 99%

SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Liu

Che

Zheng

et al. 2013

Cell Physiol Biochem

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Background: SIRT5 is located in the mitochondria, and plays a crucial role in the regulation of metabolic process and cellular apoptosis. Cardiomyocytes are abundant in mitochondria. However, the role of SIRT5 in oxidative stress-induced apoptosis is still unknown in cardiomyocytes. Methods and Results: Western blots analysis revealed that SIRT5 is significantly down-regulated in cardiomyocytes upon oxidative stress. MTT assay, DAPI staining, and caspase 3/7 activity assay were used to estimate apoptosis development. The result suggested that compared with the wild-type group, SIRT5 knockdown results in a marked reduction in cell viability, and a significant increase in the number of apoptotic cells and the caspase 3/7 activity. Protein immunoprecipitation revealed a direct interaction between Bcl-Xl and SIRT5. Apoptosis assay and western blot anaylsis suggested that SIRT5 levels could affect the levels of Bcl-Xl expression, but have no effect on the apoptosis development in Bcl-Xl knockdown cells. Conclusion: This study reveals a novel role of SIRT5 in the regulation of oxidative stress-induced apoptosis in cardiomyocytes. Pharmacological interventions on SIRT5 expression may be useful in the treatment of oxidative stress-related cardiac injury.

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Section: Discussionmentioning

confidence: 99%

SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Liu

Che

Zheng

et al. 2013

Cell Physiol Biochem

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“…Because the Ex-243 site lacks isoform-specific features, larger substitutions that can reach such isoform-specific regions will be required for improving the Sirt1 selectivity of Ex-243 or to develop compounds selective for other Sirtuins based on this binding site, and our complexes provide structural information for generating such specific interactions. The Ex-243 binding site likely also contributes to binding of other compounds, such as the Sirt2 inhibitor AGK2 (18) and the Sirt5 desuccinylation inhibitor GW5074 (25), indicating its potential to contribute to specific inhibition also of isoforms other than Sirt1. The identified mechanism and technical approaches will allow further identification of ECS inhibitors and solving of their Sirtuin complex structures to obtain further information on how to optimize binding to this site and how to add specific interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Physiological studies, target confirmation, and drug development have been hampered, however, by shortcomings of available Sirtuin inhibitors, which mostly show limited potency and/or isoform specificity and exploit unknown binding sites and mechanisms (21,22). The widely used inhibitor sirtinol, for example, has an IC 50 of 38 μM against Sirt2 and no effect on Sirt5, inhibits Sirt1 only approximately threefold weaker, and its effect on other isoforms and its mechanism are unknown (23)(24)(25). Ex-527 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; Fig.…”

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confidence: 99%

Ex-527 inhibits Sirtuins by exploiting their unique NAD ⁺ -dependent deacetylation mechanism

Gertz

Fischer

Nguyen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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281

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Sirtuins are protein deacetylases regulating metabolism and stress responses. The seven human Sirtuins (Sirt1-7) are attractive drug targets, but Sirtuin inhibition mechanisms are mostly unidentified. We report the molecular mechanism of Sirtuin inhibition by 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (Ex-527). Inhibitor binding to potently inhibited Sirt1 and Thermotoga maritima Sir2 and to moderately inhibited Sirt3 requires NAD + , alone or together with acetylpeptide. Crystal structures of several Sirtuin inhibitor complexes show that Ex-527 occupies the nicotinamide site and a neighboring pocket and contacts the ribose of NAD + or of the coproduct 2'-O-acetyl-ADP ribose. Complex structures with native alkylimidate and thio-analog support its catalytic relevance and show, together with biochemical assays, that only the coproduct complex is relevant for inhibition by Ex-527, which stabilizes the closed enzyme conformation preventing product release. Ex-527 inhibition thus exploits Sirtuin catalysis, and kinetic isoform differences explain its selectivity. Our results provide insights in Sirtuin catalysis and inhibition with important implications for drug development.

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“…Ro31-8220 induces hyperacetylation of tubulin in A549 human lung adenocarcinoma cells [132]. GW5074 (Table 6, entry 6), a nanomolar c-RAF1 kinase inhibitor, shows inhibition of SIRT2 with an IC 50 value of 15.6 μM [133] and SIRT5 with an IC 50 value of 19.5 μM [134]. However, given that these compounds are much better kinase inhibitors, the utility of them as sirtuin inhibitors may be limited.…”

Section: Sirtuin Inhibitorsmentioning

confidence: 99%

Sirtuin Inhibitors as Anticancer Agents

2014

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Sirtuins are a class of enzymes with nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacylase function. By deacylating various substrate proteins, including histones, transcription factors, and metabolic enzymes, sirtuins regulate various biological processes, such as transcription, cell survival, DNA damage and repair, and longevity. Small molecules that can inhibit sirtuins have been developed and many of them have shown anti-cancer activity. Here we summarize the major biological findings that connect sirtuins to cancer and the different types of sirtuin inhibitors developed. Interestingly, biological data suggest that sirtuins have both tumor-suppressing and tumor-promoting roles. However, most pharmacological studies with small molecule inhibitors suggest that inhibiting sirtuin is a promising anti-cancer strategy. We discuss possible explanations for this discrepancy and suggest possible future directions to further establish sirtuin inhibitors as anticancer agents.

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Inhibition of the human deacylase Sirtuin 5 by the indole GW5074

Cited by 47 publications

References 33 publications

SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Ex-527 inhibits Sirtuins by exploiting their unique NAD ⁺ -dependent deacetylation mechanism

Sirtuin Inhibitors as Anticancer Agents

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Inhibition of the human deacylase Sirtuin 5 by the indole GW5074

Cited by 47 publications

References 33 publications

SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Ex-527 inhibits Sirtuins by exploiting their unique NAD + -dependent deacetylation mechanism

Sirtuin Inhibitors as Anticancer Agents

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Ex-527 inhibits Sirtuins by exploiting their unique NAD ⁺ -dependent deacetylation mechanism