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https://www.readbyqxmd.com/read/28415012/discovery-of-2-4-6-dimethylpyrimidin-2-yl-thio-n-phenylacetamide-derivatives-as-new-potent-and-selective-human-sirtuin-2-inhibitors
#1
Lingling Yang, Xiaobo Ma, Chen Yuan, Yanying He, Ling Li, Sha Fang, Wei Xia, Tao He, Shan Qian, Zhihong Xu, Guobo Li, Zhouyu Wang
Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as SIRT2 inhibitors...
April 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28400369/in-utero-particulate-matter-exposure-produces-heart-failure-electrical-remodeling-and-epigenetic-changes-at-adulthood
#2
Vineeta Tanwar, Matthew W Gorr, Markus Velten, Clayton M Eichenseer, Victor P Long, Ingrid M Bonilla, Vikram Shettigar, Mark T Ziolo, Jonathan P Davis, Stephen H Baine, Cynthia A Carnes, Loren E Wold
BACKGROUND: Particulate matter (PM; PM2.5 [PM with diameters of <2.5 μm]) exposure during development is strongly associated with adverse cardiovascular outcomes at adulthood. In the present study, we tested the hypothesis that in utero PM2.5 exposure alone could alter cardiac structure and function at adulthood. METHODS AND RESULTS: Female FVB mice were exposed either to filtered air or PM2.5 at an average concentration of 73.61 μg/m(3) for 6 h/day, 7 days/week throughout pregnancy...
April 11, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28379698/chemically-induced-degradation-of-sirtuin-2-sirt2-by-a-proteolysis-targeting-chimera-protac-based-on-sirtuin-rearranging-ligands-sirreals
#3
Matthias Schiedel, Daniel Herp, Sören Hammelmann, Sören Swyter, Attila Lehotzky, Dina Robaa, Judit Oláh, Judit Ovádi, Wolfgang Sippl, Manfred Jung
Here we report the development of a proteolysis targeting chimera (PROTAC) based on the combination of the unique features of the sirtuin rearranging ligands (SirReals) as highly potent and isotype-selective Sirt2 inhibitors with thalidomide, a bona fide cereblon ligand. For the first time, we report the formation of a PROTAC by Cu(I)-catalyzed cycloaddition of a thalidomide-derived azide to an alkynylated inhibitor. This thalidomide-derived azide as well as the highly versatile linking strategy can be readily adapted to alkynylated ligands of other targets...
April 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28306500/catching-sirtuin-2-intermediates-one-structure-at-the-time
#4
Schuyler Lee, Zhongzhou Chen, Gongyi Zhang
Sirtuins are a large enzyme family involved in installing and removing post-translational modifications involving lysine side chains. These enzymes have been of intense research interest and we now understand many details of their mechanism, although later steps of the deacetylase activity have remained a mystery. In this issue of Cell Chemical Biology, Wang et al. (2017) capture a late intermediate of SIRT2 catalysis and describe its structure.
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28301150/discovery-of-new-sirt2-inhibitors-by-utilizing-a-consensus-docking-scoring-strategy-and-structure-activity-relationship-analysis
#5
Shenzhen Huang, Chunli Song, Xiang Wang, Guo Zhang, Yanlin Wang, Xiaojuan Jiang, Qizheng Sun, Luyi Huang, Rong Xiang, Yiguo Hu, Linli Li, Shengyong Yang
SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors...
April 24, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28299833/unsupervised-pharmacophore-modeling-combined-with-qsar-analyses-revealed-novel-low-micromolar-sirt2-inhibitors
#6
Mohammad A Khanfar, Mutasem O Taha
Situin 2 (SIRT2) enzyme is a histone deacetylase that has important role in neuronal development. SIRT2 is clinically validated target for neurodegenerative diseases and some cancers. In this study, exhaustive unsupervised pharmacophore modeling was combined with quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent SIRT2 inhibitors using 146 known SIRT2 ligands. A computational workflow that combines genetic function algorithm with k-nearest neighbor or multiple linear regression was implemented to build self-consistent and predictive QSAR models based on combinations of pharmacophores and physicochemical descriptors...
March 15, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28292463/key-players-of-the-necroptosis-pathway-ripk1-and-sirt2-are-altered-in-placenta-from-preeclampsia-and-fetal-growth-restriction
#7
Natalie J Hannan, Sally Beard, Natalie K Binder, Kenji Onda, Tu'uhevaha J Kaitu'u-Lino, Qi Chen, Laura Tuohey, Manarangi De Silva, Stephen Tong
INTRODUCTION: Preeclampsia (PE) and fetal growth restriction (FGR) are among the leading causes of perinatal morbidity and mortality. Placental insufficiency is central to these conditions. The mechanisms underlying placental insufficiency are poorly understood. Apoptosis has long been considered the only form of regulated cell death, recent research has identified an alternate process of programmed cell death known as necroptosis [1]. Necroptosis is distinct from apoptosis, relying on the deacetylase sirtuin-2 [2], receptor interacting kinases RIPK1 and 3, and the pseudokinase MLKL [3]...
March 2017: Placenta
https://www.readbyqxmd.com/read/28292429/corrigendum-to-spop-promotes-sirt2-degradation-and-suppresses-non-small-cell-lung-cancer-cell-growth-biochem-biophys-res-commun-483-2017-880-884
#8
Jie Luo, Yu-Chen Bao, Xian-Xiu Ji, Bin Chen, Qin-Fang Deng, Song-Wen Zhou
No abstract text is available yet for this article.
April 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28287409/sirtuin-2-regulates-cellular-iron-homeostasis-via-deacetylation-of-transcription-factor-nrf2
#9
Xiaoyan Yang, Seong-Hoon Park, Hsiang-Chun Chang, Jason S Shapiro, Athanassios Vassilopoulos, Konrad T Sawicki, Chunlei Chen, Meng Shang, Paul W Burridge, Conrad L Epting, Lisa D Wilsbacher, Supak Jenkitkasemwong, Mitchell Knutson, David Gius, Hossein Ardehali
SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require iron, we hypothesized that SIRT2 directly regulates cellular iron homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28286128/deacylation-mechanism-by-sirt2-revealed-in-the-1-sh-2-o-myristoyl-intermediate-structure
#10
Yi Wang, Yi Man Eva Fung, Weizhe Zhang, Bin He, Matthew Wai Heng Chung, Jing Jin, Jing Hu, Hening Lin, Quan Hao
Sirtuins are NAD-dependent deacylases. Previous studies have established two important enzymatic intermediates in sirtuin-catalyzed deacylation, an alkylamidate intermediate I, which is then converted to a bicyclic intermediate II. However, how intermediate II is converted to products is unknown. Based on potent SIRT2-specific inhibitors we developed, here we report crystal structures of SIRT2 in complexes with a thiomyristoyl lysine peptide-based inhibitor and carba-NAD or NAD. Interestingly, by soaking crystals with NAD, we capture a distinct covalent catalytic intermediate (III) that is different from the previously established intermediates I and II...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28276426/microrna-92a-is-a-circadian-modulator-of-neuronal-excitability-in-drosophila
#11
Xiao Chen, Michael Rosbash
Many biological and behavioural processes of animals are governed by an endogenous circadian clock, which is dependent on transcriptional regulation. Here we address post-transcriptional regulation and the role of miRNAs in Drosophila circadian rhythms. At least six miRNAs show cycling expression levels within the pigment dispersing factor (PDF) cell-pacemaker neurons; only mir-92a peaks during the night. In vivo calcium monitoring, dynamics of PDF projections, ArcLight, GCaMP6 imaging and sleep assays indicate that mir-92a suppresses neuronal excitability...
March 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28259910/reduced-expression-of-sirt2-in-serous-ovarian-carcinoma-promotes-cell-proliferation-through-disinhibition-of-cdk4-expression
#12
Yanhua Du, Jun Wu, Haiyan Zhang, Shaobo Li, Hong Sun
The silent information regulator 2 related enzyme 2 (SIRT2) has been reported to have an important role in tumorigenesis. Although two distinct effects of SIRT2 have recently been revealed, which explain opposing expression patterns in different types of cancer, the specific function of SIRT2 in ovarian cancer remains unknown. The present study investigated the expression of SIRT2 in serous ovarian carcinoma (SOC) and its pathogenic mechanism. It was observed that SIRT2 expression in SOC was significantly downregulated when compared with ovarian surface epithelium via western blot and immunohistochemistry...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28252048/identification-of-serum-protein-biomarkers-for-utrophin-based-dmd-therapy
#13
Simon Guiraud, Benjamin Edwards, Sarah E Squire, Arran Babbs, Nandini Shah, Adam Berg, Huijia Chen, Kay E Davies
Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures...
March 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28240897/development-of-1-2-4-oxadiazoles-as-potent-and-selective-inhibitors-of-the-human-deacetylase-sirtuin-2-structure-activity-relationship-x-ray-crystal-structure-and-anticancer-activity
#14
Sébastien Moniot, Mariantonietta Forgione, Alessia Lucidi, Gebremedhin S Hailu, Angela Nebbioso, Vincenzo Carafa, Francesca Baratta, Lucia Altucci, Nicola Giacché, Daniela Passeri, Roberto Pellicciari, Antonello Mai, Clemens Steegborn, Dante Rotili
Sirt2 is a target for the treatment of neurological, metabolic, and age-related diseases including cancer. Here we report a series of Sirt2 inhibitors based on the 1,2,4-oxadiazole scaffold. These compounds are potent Sirt2 inhibitors active at single-digit μM level by using the Sirt2 substrate α-tubulin-acetylLys40 peptide and inactive up to 100 μM against Sirt1, -3, and -5 (deacetylase and desuccinylase activities). Their mechanism of inhibition is uncompetitive toward both the peptide substrate and NAD(+), and the crystal structure of a 1,2,4-oxadiazole analog in complex with Sirt2 and ADP-ribose reveals its orientation in a still unexplored subcavity useful for further inhibitor development...
March 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28188285/rna-binding-protein-quaking-stabilizes-sirt2-mrna-during-oligodendroglial-differentiation
#15
Merlin P Thangaraj, Kendra L Furber, Jotham K Gan, Shaoping Ji, Larhonda Sobchishin, J Ronald Doucette, Adil J Nazarali
Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Sirtuin 2 (SIRT2), a NAD(+)-dependent deacetylase, plays a critical role in OL differentiation by promoting both arborization and downstream expression of myelin-specific genes. However, the mechanisms involved in regulating SIRT2 expression during OL development are largely unknown. The RNA-binding protein quaking (QKI) plays an important role in myelination by post-transcriptionally regulating the expression of several myelin specific genes...
March 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28185898/sirt2-inhibition-modulate-glutamate-and-serotonin-systems-in-the-prefrontal-cortex-and-induces-antidepressant-like-action
#16
Mercedes Erburu, Irene Muñoz-Cobo, Teresa Diaz-Perdigon, Paolo Mellini, Takayoshi Suzuki, Elena Puerta, Rosa M Tordera
Growing evidence suggests that changes in histone acetylation in specific sites of the chromatin modulate neuronal plasticity and contribute to antidepressant-like action. Sirtuin 2 (SIRT2) is a class III NAD(+)-dependent histone deacetylase involved in transcriptional repression of genes regulating synaptic plasticity. Importantly, a key role for the glutamate system in prefrontal cortex (PFC) synaptic plasticity changes induced by antidepressants has been suggested. Here, we asked whether SIRT2 could be a pharmacological target for depression therapy...
February 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28166441/expression-profile-of-sirt2-in-human-melanoma-and-implications-for-sirtuin-based-chemotherapy
#17
Melissa Jean Wilking-Busch, Mary Ann Ndiaye, Wei Huang, Nihal Ahmad
Melanoma is cancer of melanin-containing melanocyte cells. This neoplasm is one of the most deadly forms of skin cancer, and currently available therapeutic options are insufficient in significantly improve outcomes for many patients. Therefore, novel targets are required to effectively manage this neoplasm. Several sirtuins have previously been found to be upregulated in melanoma, so in this study, the expression profile of SIRT2 was determined. Employing a tissue microarray containing benign nevi, primary melanomas, and lymph node metastases, we have found that the tissue from lymph node metastases appears to have a significant upregulation of SIRT2 relative to primary tumors across the nuclear, cytoplasmic, and whole cell data...
March 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28135086/thienopyrimidinone-based-sirtuin-2-sirt2-selective-inhibitors-bind-in-the-ligand-induced-selectivity-pocket
#18
Sandeep Sundriyal, Sébastien Moniot, Zimam Mahmud, Shang Yao, Paolo Di Fruscia, Christopher R Reynolds, David T Dexter, Michael J E Sternberg, Eric W-F Lam, Clemens Steegborn, Matthew J Fuchter
Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity...
March 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28127057/sirtinol-promotes-pepck1-degradation-and-inhibits-gluconeogenesis-by-inhibiting-deacetylase-sirt2
#19
Mingming Zhang, Yida Pan, Robert G Dorfman, Yuyao Yin, Qian Zhou, Shan Huang, Jie Liu, Shimin Zhao
Phosphoenolpyruvate carboxykinase 1 (PEPCK1) is the critical enzyme for gluconeogenesis and is linked with type II diabetes. Previous studies have found that SIRT2, a deacetylase, plays an important role in deacetylating PEPCK1 and little is known about the anti-diabetic activity of SIRT2 inhibitors. In this study, we investigated the anti-diabetic effects of sirtinol, a SIRT2 inhibitor, on cell gluconeogenesis in vivo and in vitro. Immunoblotting analysis revealed that sirtinol significantly decreased the protein level of PEPCK1, and was accompanied by the hyperacetylation of PEPCK1 as well as decreased glucose output in a dose-dependent manner...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28103679/histone-ketoamide-adduction-by-4-oxo-2-nonenal-is-a-reversible-posttranslational-modification-regulated-by-sirt2
#20
LETTER
Yiwen Cui, Xin Li, Jianwei Lin, Quan Hao, Xiang David Li
Lipid-derived electrophiles (LDEs) directly modify proteins to modulate cellular signaling pathways in response to oxidative stress. One such LDE, 4-oxo-2-nonenal (4-ONE), has recently been found to target histones and interfere with histone assembly into nucleosomes. Unlike other LDEs that preferentially modify cysteine via nucleophilic Michael addition, 4-ONE reacts with histone lysine residues to form a new histone modification, gamma-oxononanoylation (Kgon). However, it remains unclear whether Kgon can cause irreversible damage or be regulated by enzymes "erasing" this nonenzymatic modification...
January 20, 2017: ACS Chemical Biology
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