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Hening Lin - One of the best experts on this subject based on the ideXlab platform.
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a small molecule sirt2 inhibitor that promotes k ras4a lysine fatty acylation
2019Co-Authors: Nicole A Spiegelman, Hui Jing, Hening Lin, Jun Young Hong, Miao Wang, Ian R. Price, Ji Cao, Min Yang, Xiaoyu ZhangAbstract:SIRT2, a member of the sirtuin family of protein lysine deacylases, has been identified as a promising therapeutic target for treating cancer. In addition to catalyzing deacetylation, SIRT2 has recently been shown to remove fatty acyl groups from K-Ras4a and promote its transforming activity. Among the SIRT2-specific inhibitors, only the thiomyristoyl lysine compound TM can weakly inhibit the demyristoylation activity of SIRT2. Therefore, more potent small-molecule SIRT2 inhibitors are needed to further evaluate the therapeutic potential of SIRT2 inhibition, and to understand the function of protein lysine defatty-acylation. Herein we report a SIRT2 inhibitor, JH-T4, which can increase K-Ras4a lysine fatty acylation. This is the first small-molecule inhibitor that can modulate the lysine fatty acylation levels of K-Ras4a. JH-T4 also inhibits SIRT1 and SIRT3 in vitro. The increased potency of JH-T4 is likely due to the formation of hydrogen bonding between the hydroxy group and SIRT1, SIRT2, and SIRT3. This is further supported by in vitro studies with another small-molecule inhibitor, NH-TM. These studies provide useful insight for future SIRT2 inhibitor development.
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SIRT7 is activated by dna and deacetylates histone h3 in the chromatin context
2016Co-Authors: Zhen Tong, Quan Hao, Xiaoyu Zhang, Yi Wang, David D Kim, Sushabhan Sadhukhan, Hening LinAbstract:Mammalian sirtuins (SIRT1–7) are members of a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate many biological processes including metabolism, genome stability, and transcription. Among the seven human sirtuins, SIRT7 is the least understood, to a large extent due to the lack of enzymatic activity in vitro. Here, we reported that SIRT7 can be activated by DNA to hydrolyze the acetyl group from lysine residues in vitro on histone peptides and histones in the chromatin context. Both N- and C- termini of SIRT7 are important for the DNA-activated deacetylase activity. The regulatory mechanism of SIRT7 is different from that of SIRT6, which also showed increased activity on chromatin substrates, but the deacetylase activity of SIRT6 on a peptide substrate cannot be activated by DNA. This finding provides an improved enzymatic activity assay of SIRT7 that will promote the development of SIRT7 modulators. Further investigation into the activation me...
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an improved fluorogenic assay for sirt1 sirt2 and sirt3
2016Co-Authors: Yingling Chiang, Hening LinAbstract:Sirtuins are NAD-dependent lysine deacylases that play critical roles in cellular regulation and are implicated in human diseases. Modulators of sirtuins are needed as tools for investigating their biological functions and possible therapeutic applications. However, the discovery of sirtuin modulators is hampered by the lack of efficient sirtuin assays. Here we report an improved fluorogenic assay for SIRT1, SIRT2, and SIRT3 using a new substrate, a myristoyl peptide with a C-terminal aminocoumarin. The new assay has several advantages, including significantly lower substrate concentration needed, increased signal-to-background ratio, and improved Z'-factor. The novel assay thus will expedite high-throughput screening of SIRT1, SIRT2, and SIRT3 modulators.
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efficient demyristoylase activity of sirt2 revealed by kinetic and structural studies
2015Co-Authors: Yanbin Teng, Hui Jing, Pornpun Aramsangtienchai, Saba Khan, Hening Lin, Quan HaoAbstract:Sirtuins are a class of enzymes originally identified as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases. Among the seven mammalian sirtuins, SIRT1-7, only SIRT1-3 possess efficient deacetylase activity in vitro, whereas SIRT4-7 possess very weak in vitro deacetylase activity. Several sirtuins that exhibit weak deacetylase activity have recently been shown to possess more efficient activity for the removal other acyl lysine modifications, such as succinyl lysine and palmitoyl lysine. Here, we demonstrate that even the well-known deacetylase SIRT2 possesses efficient activity for the removal of long-chain fatty acyl groups. The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group. The crystal structure of SIRT2 in complex with a thiomyristoyl peptide reveals that SIRT2 possesses a large hydrophobic pocket that can accommodate the myristoyl group. Comparison of the SIRT2 acyl pocket to those of SIRT1, SIRT3, and SIRT6 reveals that the acyl pockets of SIRT1-3 are highly similar, and to a lesser degree, similar to that of SIRT6. The efficient in vitro demyristoylase activity of SIRT2 suggests that this activity may be physiologically relevant and warrants future investigative studies.
John M Denu - One of the best experts on this subject based on the ideXlab platform.
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kinetic and structural basis for acyl group selectivity and nad dependence in sirtuin catalyzed deacylation
2015Co-Authors: Jessica L Feldman, Kristin E Dittenhaferreed, Norio Kudo, Julie N Thelen, Akihiro Ito, Minoru Yoshida, John M DenuAbstract:Acylation of lysine is an important protein modification regulating diverse biological processes. It was recently demonstrated that members of the human Sirtuin family are capable of catalyzing long chain deacylation, in addition to the well-known NAD+-dependent deacetylation activity [Feldman, J. L., Baeza, J., and Denu, J. M. (2013) J. Biol. Chem. 288, 31350–31356]. Here we provide a detailed kinetic and structural analysis that describes the interdependence of NAD+-binding and acyl-group selectivity for a diverse series of human Sirtuins, SIRT1–SIRT3 and SIRT6. Steady-state and rapid-quench kinetic analyses indicated that differences in NAD+ saturation and susceptibility to nicotinamide inhibition reflect unique kinetic behavior displayed by each Sirtuin and depend on acyl substrate chain length. Though the rate of nucleophilic attack of the 2′-hydroxyl on the C1′-O-alkylimidate intermediate varies with acyl substrate chain length, this step remains rate-determining for SIRT2 and SIRT3; however, for SI...
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Kinetic and Structural Basis for Acyl-Group Selectivity and NAD+ Dependence in Sirtuin-Catalyzed Deacylation
2015Co-Authors: Jessica L. Feldman, Norio Kudo, Akihiro Ito, Minoru Yoshida, Kristin E. Dittenhafer-reed, Julie N. Thelen, John M DenuAbstract:Acylation of lysine is an important protein modification regulating diverse biological processes. It was recently demonstrated that members of the human Sirtuin family are capable of catalyzing long chain deacylation, in addition to the well-known NAD+-dependent deacetylation activity [Feldman, J. L., Baeza, J., and Denu, J. M. (2013) J. Biol. Chem. 288, 31350–31356]. Here we provide a detailed kinetic and structural analysis that describes the interdependence of NAD+-binding and acyl-group selectivity for a diverse series of human Sirtuins, SIRT1–SIRT3 and SIRT6. Steady-state and rapid-quench kinetic analyses indicated that differences in NAD+ saturation and susceptibility to nicotinamide inhibition reflect unique kinetic behavior displayed by each Sirtuin and depend on acyl substrate chain length. Though the rate of nucleophilic attack of the 2′-hydroxyl on the C1′-O-alkylimidate intermediate varies with acyl substrate chain length, this step remains rate-determining for SIRT2 and SIRT3; however, for SIRT6, this step is no longer rate-limiting for long chain substrates. Cocrystallization of SIRT2 with myristoylated peptide and NAD+ yielded a co-complex structure with reaction product 2′-O-myristoyl-ADP-ribose, revealing a latent hydrophobic cavity to accommodate the long chain acyl group, and suggesting a general mechanism for long chain deacylation. Comparing two separately determined co-complex structures containing either a myristoylated peptide or 2′-O-myristoyl-ADP-ribose indicates there are conformational changes at the myristoyl–ribose linkage with minimal structural differences in the enzyme active site. During the deacylation reaction, the fatty acyl group is held in a relatively fixed position. We describe a kinetic and structural model to explain how various Sirtuins display unique acyl substrate preferences and how different reaction kinetics influence NAD+ dependence. The biological implications are discussed
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activation of the protein deacetylase sirt6 by long chain fatty acids and widespread deacylation by mammalian sirtuins
2013Co-Authors: Jessica L Feldman, Josue Baeza, John M DenuAbstract:Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD+-dependent protein deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long-chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor deacetylase in vitro, but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small-molecule activators of SIRT6.
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activation of the protein deacetylase sirt6 by long chain fatty acids and widespread deacylation by mammalian sirtuins
2013Co-Authors: Jessica L Feldman, Josue Baeza, John M DenuAbstract:Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD+-dependent protein deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long-chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor deacetylase in vitro, but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small-molecule activators of SIRT6. Background: Sirtuins regulate metabolism, genome maintenance, and stress responses. Results: Long-chain free fatty acids stimulate SIRT6 deacetylase, and sirtuins display distinct but overlapping specificity for diverse acylated peptides. Conclusion: SIRT6 is activated by biologically relevant fatty acids, and long-chain deacylation is a general feature of sirtuins. Significance: Discovery of endogenous, small-molecule activators of SIRT6 demonstrates the therapeutic potential of compounds that promote SIRT6 function.
Liqiang Chen - One of the best experts on this subject based on the ideXlab platform.
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5 3 amidobenzyl oxy nicotinamides as sirtuin 2 inhibitors
2016Co-Authors: Teng Ai, Swati S More, Daniel J Wilson, Liqiang ChenAbstract:Derived from our previously reported human sirtuin 2 (SIRT2) inhibitors that were based on a 5-aminonaphthalen-1-yloxy nicotinamide core structure, 5-((3-amidobenzyl)oxy)nicotinamides offered excellent activity against SIRT2 and high isozyme selectivity over SIRT1 and SIRT3. Selected compounds also exhibited generally favorable in vitro absorption, distribution, metabolism, and excretion properties. Kinetic studies revealed that a representative SIRT2 inhibitor acted competitively against both NAD+ and the peptide substrate, an inhibitory modality that was supported by our computational study. More importantly, two selected compounds exhibited significant protection against α-synuclein aggregation-induced cytotoxicity in SH-SY5Y cells. Therefore, 5-((3-amidobenzyl)oxy)nicotinamides represent a new class of SIRT2 inhibitors that are attractive candidates for further lead optimization in our continued effort to explore selective inhibition of SIRT2 as a potential therapy for Parkinson’s disease.
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discovery of potent and selective sirtuin 2 sirt2 inhibitors using a fragment based approach
2014Co-Authors: Zeeshan Kamal, Teng Ai, Swati S More, Yanli Xu, Daniel J Wilson, Liqiang ChenAbstract:Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD+-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene–benzamides and −nicotinamides. Biochemical evaluation of these two series provided structure–activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both...
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discovery of potent and selective sirtuin 2 sirt2 inhibitors using a fragment based approach
2014Co-Authors: Huaqing Cui, Swati S More, Zeeshan Kamal, Daniel J Wilson, Liqiang ChenAbstract:Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.
Leo I Gordon - One of the best experts on this subject based on the ideXlab platform.
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functional characterization of nad dependent de acetylases sirt1 and sirt2 in b cell chronic lymphocytic leukemia cll
2016Co-Authors: Savita Bhalla, Leo I GordonAbstract:ABSTRACTSirtuins (SIRT) are nicotinamide adenine dinucleotide (NAD+) dependent deacetylases or ADP- ribosyl transferases (ARTs) that deacetylate lysine residues on various proteins regulating a variety of cellular and metabolic processes. These enzymes regulate metabolism, cell survival, differentiation and DNA repair. SIRT proteins play an important role in the survival and drug resistance of cancer cells. The purpose of the present study was to investigate the expression and role of SIRT in chronic lymphocytic leukemia (CLL). We analyzed the expression of SIRT1 and SIRT2 in CLL and normal B cells using the Oncomine database as well as by Western blotting of fresh CLL cells from patients and pro-lymphocytic leukemia (PLL) cell lines, JVM-3 and MEC-2. We showed that both primary CLL cells and JVM-3 and MEC-2 cell lines overexpress high levels of functional SIRT1 and SIRT2. SIRT inhibitors EX-527 and sirtinol impair cell growth, induce ROS production, loss of mitochondrial membrane potential and apoptosis ...
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functional characterization of nad dependent de acetylases sirt1 and sirt2 in b cell chronic lymphocytic leukemia cll
2015Co-Authors: Savita Bhalla, Leo I GordonAbstract:Introduction: CLL is characterized by abnormal proliferation and accumulation of mature CD5 positive B-lymphocytes in blood, bone marrow, spleen and lymph nodes. Outcome and survival is determined in part by the presence of 11q deletions and17p deletion/ TP53 mutation with complex karyotype. Sirtuins are NAD+ dependent ADP-ribosyl transferases with evolutionary conserved function in cellular metabolism and chromatin regulation. Seven sirtuins (SIRT1-SIRT7) have been identified in mammals at distinct subcellular locations and targeting different substrates. SIRT1, 2, 6, and 7 are primarily found in the nucleus, SIRT2 in the cytoplasm and SIRT3, 4, 5 in the mitochondria. Sirtuins are associated with cancer as they deacetylate cancer associated transcription factors, and SIRT1 is overexpressed in acute myeloid leukemia, colon and prostate cancers. Several studies reported SIRT2 as a tumor suppressor as it is down regulated in human gliomas. SIRT1 and SIRT6 are reported to be significantly increased in CLL. We hypothesized that sirtuins play an important role in the development and maintenance of CLL and might therefore be a target. Methods: We measured SIRT 1 and 2 expression in fresh primary CLL cells, in the B-cell pro-lymphocytic cell lines JVM-3 and MEC-2 and by data-mining of the Oncomine microarray gene expression datasets. Oncomine is a bioinformatics initiative that collects, standardizes, analyzes, and delivers cancer transcriptome data to the biomedical research community. We then inhibited SIRT activity in primary CLL cells and cell lines by pharmacologic inhibitors EX-529 and sirtinol, and by knock down using shRNA in cell lines and then measured cell viability, apoptosis, reactive oxygen species formation and mitochondrial membrane potential. To determine the metabolic contribution to SIRT activity, we studied the effect of SIRT inhibition under conditions of nutrient deprivation. Results: We observed an increase in SIRT1mRNA expression in CLL by data mining of the independent microarray dataset in the Oncomine database, with a total of 2022 leukemia samples and 74 normal controls (Figure1). SIRT1was significantly up regulated in CLL compared with normal PBMC as well as other leukemia types. We found that SIRT inhibitors EX-527 and sirtinol impair cell growth (IC50 50-100 microM for EX-527 and 10-20 microM for sirtinol), cause apoptosis (>2-fold increase in apoptosis in cell lines JVM-3 and MEC-2), induce ROS production (up to 90% increase in mean fluorescence intensity (MFI) with EX-527 and sirtinol), loss of mitochondrial membrane potential, (MFI from 4 to <1 after treatment with SIRT inhibitors) and increase alpha-tubulin acetylation in primary CLL cells and cell lines. Using shRNA knock down of SIRT1 and SIRT2 in JVM-3 and MEC-2 cell lines, we showed that expression of both proteins is crucial for the survival of these cells. Furthermore, studies in nutrient deprived conditions suggest a role of SIRT in metabolism in CLL. Conclusion: These findings suggest that CLL cells are characterized by increased expression and function of SIRT1 and SIRT2, both directly inhibited by SIRT inhibitors. SIRT1 and SIRT2 inhibition using specific inhibitors could be a novel therapeutic approach for the treatment of CLL and other SIRT expressing hematologic malignancies. ![Figure 1.][1] Figure 1. Disclosures Gordon: Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending. [1]: pending:yes
Richard B Silverman - One of the best experts on this subject based on the ideXlab platform.
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design and evaluation of 3 benzylthio benzamide derivatives as potent and selective sirt2 inhibitors
2015Co-Authors: Mohammad A Khanfar, Luisa Quinti, Aleksey G Kazantsev, Hua Wang, Johnathan Nobles, Richard B SilvermanAbstract:Inhibitors of sirtuin-2 (SIRT2) deacetylase have been shown to be protective in various models of Huntington’s disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the 3-(benzylsulfonamido)benzamide scaffold and improving their metabolic stability. Molecular modeling and docking studies revealed an unfavorable role of the sulfonamide moiety for SIRT2 binding. This prompted us to replace the sulfonamide with thioether, sulfoxide, or sulfone groups. The thioether analogues were the most potent SIRT2 inhibitors with a two- to three-fold increase in potency relative to their corresponding sulfonamide analogues. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. Two thioether-derived compounds (17 and 18) increased α-tubulin acetylation in a dose-dependent manner in at least one neuronal cell line, and 18 was found to inhibit polyglutamine aggregatio...
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development and characterization of 3 benzylsulfonamido benzamides as potent and selective sirt2 inhibitors
2014Co-Authors: Soo Hyuk Choi, Luisa Quinti, Aleksey G Kazantsev, Mohammad A Khanfar, Hua Wang, Richard B SilvermanAbstract:Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
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3 n arylsulfamoyl benzamides inhibitors of human sirtuin type 2 sirt2
2012Co-Authors: Soo Hyuk Choi, Luisa Quinti, Aleksey G Kazantsev, Richard B SilvermanAbstract:Abstract Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson’s and Huntington’s models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-( N -arylsulfamoyl)benzamide scaffold, including3-( N -(4-bromophenyl)sulfamoyl)- N -(4-bromophenyl)benzamide( C2 – 8 , 1a ), which demonstrated neuroprotective effects in a Huntington’s mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure–activity relationships observed for 1a analogs and docking simulation data suggest that the para -substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.
