Identification of novel SIRT3 inhibitor scaffolds by virtual screening

Salo, Heikki S.; Laitinen, Tuomo; Poso, Antti; Jarho, Elina; Lahtela‐Kakkonen, Maija

doi:10.1016/j.bmcl.2013.03.033

Cited by 32 publications

(22 citation statements)

References 27 publications

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“…Our immunoprecipitation data further revealed that insulin resistance promoted PGC-1 acetylation, the effect of which may be reversed by ALDH2. These data revealed that cardiac dysfunction under sucrose diet-induced insulin resistance is probably the result of decreased nuclear genes encoding mitochondrial proteins as a result of PGC-1α acetylation [42]. Our in vitro insulin resistant model confirmed that the benefit of Alda-1 may be nullified by the Sirt-3 inhibitor 5-amino-2-(4-aminophenyl)benzoxazole.…”

Section: Discussionsupporting

confidence: 68%

Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α

Ren

Zhang

2016

Oncotarget

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Insulin resistance contributes to the high prevalence of type 2 diabetes mellitus, leading to cardiac anomalies. Emerging evidence depicts a pivotal role for mitochondrial injury in oxidative metabolism and insulin resistance. Mitochondrial aldehyde dehydrogenase (ALDH2) is one of metabolic enzymes detoxifying aldehydes although its role in insulin resistance remains elusive. This study was designed to evaluate the impact of ALDH2 overexpression on insulin resistance-induced myocardial damage and mechanisms involved with a focus on autophagy. Wild-type (WT) and transgenic mice overexpressing ALDH2 were fed sucrose or starch diet for 8 weeks and cardiac function and intracellular Ca2+ handling were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate Akt, heme oxygenase-1 (HO-1), PGC-1α and Sirt-3. Our data revealed that sucrose intake provoked insulin resistance and compromised fractional shortening, cardiomyocyte function and intracellular Ca2+ handling (p < 0.05) along with unaltered cardiomyocyte size (p > 0.05), mitochondrial injury (elevated ROS generation, suppressed NAD+ and aconitase activity, p < 0.05 for all), the effect of which was ablated by ALDH2. In vitro incubation of the ALDH2 activator Alda-1, the Sirt3 activator oroxylin A and the histone acetyltransferase inhibitor CPTH2 rescued insulin resistance-induced changes in aconitase activity and cardiomyocyte function (p < 0.05). Inhibiting Sirt3 deacetylase using 5-amino-2-(4-aminophenyl) benzoxazole negated Alda-1-induced cardioprotective effects. Taken together, our data suggest that ALDH2 serves as an indispensable cardioprotective factor against insulin resistance-induced cardiomyopathy with a mechanism possibly associated with facilitation of the Sirt3-dependent PGC-1α deacetylation.

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Section: Discussionsupporting

confidence: 68%

Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α

Ren

Zhang

2016

Oncotarget

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“…59 Also, under the guidance of a virtual screening workflow based on shape matching and docking, a novel SIRT3 inhibitor with scaffolds, with the name of 5-amino-2-phenyl-benzoxazole has been discovered, which may provide a good starting point for future development of SIRT3 inhibitors with a novel structural scaffold. 60 …”

Section: Sirt3 a Therapeutic Target In Cancermentioning

confidence: 99%

Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer

et al. 2014

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Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, may target mitochondrial proteins for lysine deacetylation and also regulate cellular functions. And, SIRT3 is an emerging instrumental regulator of the mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. Accumulating evidence has recently demonstrated that SIRT3 may function as either oncogene or tumor suppressor on influencing cell death by targeting a series of key modulators and their relevant pathways in cancer. Thus, in this review, we present the structure, transcriptional regulation, and posttranslational modifications of SIRT3. Subsequently, we focus on highlighting the Janus role of SIRT3 with oncogenic or tumor-suppressive function in cancer, which may provide more new clues for exploring SIRT3 as a therapeutic target for drug discovery.

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“…[25] Lahtela-Kakkonen andc o-workersp erformed av irtual screening workflow by using shape-based filtering and af lexible docking protocola nd found the 5-amino-2-phenyl-benzoxazoles caffold to be suitable for furthers tructure-activity studies. [26] Compound 7 was found to be most potent inhibitor of SIRT3 (71 %i nhibition,F igure 5).…”

Section: Non-kinase Inhibitorsmentioning

confidence: 98%

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

et al. 2015

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In recenty ears, the emergence of biologically active compounds that contain ah eterocyclic ring has gained ag reat deal of attention among medicinal chemists. Among these, benzoxazole-based compounds are particularly attractive because of their wide range of pharmacological activities. In this focus review, we highlight recent advancements in the development of benzoxazole-based pharmacologically active compounds since the year 2000.

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Identification of novel SIRT3 inhibitor scaffolds by virtual screening

Cited by 32 publications

References 27 publications

Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α

Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α

Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

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