Review
Sirtuin modulators: an updated patent review (2012 -- 2014) Paolo Mellini, Sergio Valente & Antonello Mai† 2.
SIRT1--7 and their biological relevance in diseases: a brief update from literature
3.
Sirtuin modulators, patents
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Chulalongkorn University on 01/03/15 For personal use only.
2012 -- 2014 4.
Expert opinion
†
Department of Drug Chemistry and Technologies, Sapienza Universit a di Roma, Istituto PasteurFondazione Cenci Bolognetti, Rome, Italy
Introduction: Since 2000 sirtuins (SIRT1--7) have gained growing attention for their connections with many biological processes such as cellular metabolism regulation, neuroprotection, apoptosis, inflammation, and cancer progression. In particular, SIRT1 has been the most studied isoform, not only for its role during caloric restriction but also as target in prevention of aging-related diseases. SIRT inhibition can be useful for treating cancer, HIV infection or muscular diseases, SIRT activation can exert positive effects in aging-related disorders such as metabolism, cardiovascular, and neurodegenerative diseases. Areas covered: This review includes the patents about sirtuin modulation released during the 2012 -- 2014 period, and covers the potential therapeutic uses of known sirtuin modulators as well as new related small molecules in various disease contexts. Expert opinion: The effective role of sirtuins in cancer is still controversial, because some of them seem to have tumor-promoter as well as tumorsuppressor properties. Thus, few patents describing SIRT inhibitors have been found in 2012 -- 2014 period. Despite the still active debate on their role as direct or indirect activators of SIRT1, sirtuin-activating compounds are actually subjected to intense research for the ability to treat neurodegenerative diseases, metabolic disorders, inflammation, vascular system injuries, wound healing and endothelial dysfunctions. A great number of clinical trials are reported with either SIRT inhibitors or activators, thus it is possible that in the foreseeable future one or more of them will enter in the clinical arena. Keywords: diabetes, epigenetics, inflammation, obesity, sirtuins, small molecule activators Expert Opin. Ther. Patents (2015) 25(1):5-15
In this review, after an introduction on sirtuins and their biological roles in diseases, we examined all the patents reported in literature in the years 2012 -- 2014 describing new therapeutic applications as well as novel small molecules related to sirtuin modulators. Bibliographic research was carried out using Espacenet and SciFinder. Only patents published in English have been considered. 1.
Introduction
Sirtuins belong to the class III histone deacetylases (HDACs) and are NAD+-dependent enzymes [1]. From yeast to humans, they contain a highly conserved catalytic core domain formed by 275 amino acids, and N,C-terminal extensions variable in length and sequence that can (1) affect the binding with interacting partners, (2) mediate interactions with other sirtuin forms, and (3) direct cellular localization. In mammals there are seven sirtuin isoforms (SIRT1--7) able to catalyze specific lysine substrate deacetylation/deacylation [1]. Among them, SIRT4 and SIRT6 possess mainly NAD+-dependent mono-ADP-ribosyltransferase activity, SIRT5 has been reported to have potent demalonylase/desuccinylase activity [2], and other deacylation reactions can be catalyzed by SIRT6 [3]. The seven SIRT1--7 isoforms are differently located 10.1517/13543776.2014.982532 © 2015 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. .
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A key introduction through a novel update from literature that shows each promising therapeutic application of sirtuin modulators. The patents’ production in the field of sirtuin modulators in the years 2012 -- 2014 was examined. The activity of known dual SIRT1/2 inhibitors and SIRT1 activators was evaluated and found beneficial not only in reducing virus production but also as promising strategy for metabolic as well as neurodegenerative diseases. A large number of compounds bearing different bicyclic moieties including phenylquinazolinones, phenylimidazo [1,2-b]pyridazines, phenyl-[1,2,4]triazolo[4,3-b] pyridazines, phenylpyrazolo[1,5-a]pyrimidines, quinolines, quinazolines and pyrido[3,2-d]pyrimidines were described as SIRT1 activators. Despite the debate on their direct or indirect mechanism of SIRT activation is still open, their phenotypic effects on positive regulation in metabolism and cardiovascular diseases and in neurodegeneration seem to be undoubted.
This box summarizes key points contained in the article.
within cellular compartments depending on cell type, stress conditions and interaction with other proteins [4]. SIRT1, SIRT6, and SIRT7 are typically nuclear enzymes, with SIRT7 preferentially located into nucleolus. SIRT1 can be also found in cytoplasm, where SIRT2 is predominantly located. SIRT3, -4, and -5 are localized in the mitochondria, but SIRT3 localization is still debated because of its potential translocation to the nucleus under cellular stress conditions [1]. For deacetylation, sirtuins can accept histone as well as a number of non-histone substrates [5], and it can explain the wide biological processes in which these enzymes are involved, ranging from metabolic, cardiovascular and neurodegenerative diseases to cancer development and progression.
SIRT1--7 and their biological relevance in diseases: a brief update from literature
2.
Sirtuins and metabolic functions SIRT1 is directly involved on metabolic pathways such as lipogenesis, stimulation of fatty acid b-oxidation, and gluconeogenesis. Its overexpression is thought to be beneficial and generates phenotypes in mice similar to calorie restriction conditions. All the major mitochondrial processes including the Krebs cycle, the fatty acid metabolism, the antioxidant response, the amino acid catabolism, and so on, are regulated by the balance of N"-lysine acetylation/deacetylation. SIRT3, the most well-characterized mitochondrial sirtuin, shows a robust deacetylase activity. SIRT3 exists as a nuclear full length form FL-SIRT3 that is processed as a result of cellular stress to the short mitochondrial form. Nuclear FL-SIRT3 [6] exhibits deacetylase activity coherently with the fact that SIRT3 regulates the expression and activity of nuclear genes 2.1
6
such as peroxisome proliferator-activated receptor-g coactivator-1a and manganese superoxide dismutase, and modulates forkhead box O3 (FOXO3a) by direct deacetylation. SIRT3 may regulate cellular energy status both at transcriptional level in the nucleus and by posttranscriptional mechanisms in mitochondria, and its expression is higher in metabolically active tissues including brain, liver, heart, brown adipose tissue and skeletal muscle [7]. SIRT4 is located in the mitochondrial matrix and exhibits prevalently ADP-ribosylase and a weak deacetylase activity. Little is known about the physiological relevance of SIRT4 and its role in metabolism. Recently, Haigis and coworkers [8] showed that SIRT4 promoted lipid synthesis and inhibition of fatty acid oxidation by deacetylation of malonyl CoA decarboxylase, an enzyme that produces acetyl-CoA from malonyl-CoA. SIRT5 has weak deacetylase activity, one of the substrate reported to be deacetylated being CPS1 (carbamoyl phosphatase 1), a key enzyme of the urea cycle. Deacetylation of CPS1 by SIRT5 was found to improve ammonia detoxification. Recently, Lin and co-workers [2] showed that SIRT5 has potent demalonylation and desuccinylation enzymatic activity, and that CPS1, isocitrate dehydrogenase 2, glutamate dehydrogenase and 3-hydroxy-3-methylglutaryl-CoA synthase 2 are subjected to these post-translational modifications. The involvement of SIRT5 in metabolic pathways needs to further investigation. The first indication of the connection between SIRT6 and metabolism was provided by Mostoslavsky et al. [9] who showed that SIRT6-deficient mice had a loss of subcutaneous fat, lymphopenia and acute hypoglycemia. Sirtuins and cancer Among the sirtuin family, the involvement of SIRT1 in cancer is the most studied and it is decisively controversial and contradictory. SIRT1 normally protects cells from oncogenic transformation, but on the other side its enzymatic activity can promote cancer growth by deacetylation/inactivation of proapoptotic factors [10,11]. SIRT1 is overexpressed in different kinds of tumors such as prostate, breast, lung, hepatocellular, neuroblastoma, lymphoma and leukemia, colorectal, pancreatic, and gastric cancers. During tumorigenesis, SIRT2 also can function as both tumor promoter and suppressor, this behavior seeming to be dependent on the cellular context. The expression of SIRT2 has been found downregulated in several cancers (such as gliomas, breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, and esophageal adenocarcinoma), and elevated in others (such as neuroblastoma, pancreatic cancer, and acute myeloid leukemia) [13,14]. Several studies highlight a prosurvival role for SIRT3 in both normal and cancer cells, in which SIRT3 seems to control proliferative and survival pathways. Recently, SIRT3 has been found overexpressed in head and neck squamous cell carcinoma, where it regulates reactive oxygen species to a level able to maintain a proliferative and aggressive cell phenotype and to prevent apoptosis [15]. A proapoptotic role has also been proposed, but this dualism tumor promoter/suppressor showed by SIRT3 needs further 2.2
Expert Opin. Ther. Patents (2015) 25(1)
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Chulalongkorn University on 01/03/15 For personal use only.
Sirtuin modulators: an updated patent review (2012 -- 2014)
investigations. Growing evidences show that SIRT6 is a tumor suppressor protein [16]. SIRT6 involvement in cancer progression is mainly its ability to regulate metabolic functions. Tumor cells need to readjust their energy metabolism to fuel cell growth and division, and glucose metabolism is the best known example of metabolic reprogramming in cancer cells. SIRT6 regulates aerobic glycolysis in cancer cells, and SIRT6-deficient cells develop cancer regardless of oncogene activation [17]. The nucleolar SIRT7 exists also as a cytoplasmic form, and has been supported to play a crucial role in oxidative and genotoxic stress response. SIRT7 is more abundant in highly proliferative than in lowly proliferative tissues, and a role for SIRT7 as activator of proliferation has been proposed. SIRT7 was reported to be upregulated in breast and thyroid cancers, and the consequent H3K18 hypoacetylation was considered a marker of malignancy [18]. Sirtuins and neurodegenerative disease Alzheimer’s disease (AD) is one of the most common and devastating age-related neurodegenerative diseases. In in vitro models the expression of SIRT1 protects microglia cells through the inhibition of nuclear factor kappa B (NF-kB) signaling by deacetylation at Lys310 of its RelA/p65 subunit [19]. AD in the APPswe/PS1dE9 mouse model (Ab plaque formation and learning and memory deficits) was mitigated by SIRT1 overexpression and exacerbated in mice with SIRT1knocked out in the brain. Huntington’s disease (HD) is a neurodegenerative genetic polyglutamine (polyQ) disorder. The disease is caused by an autosomal dominant mutation of two copies of a gene called Huntingtin, which gradually damages cells in the brain. In a C. elegans model for HD, the promotion of Sir2 activity was found protective against the early phases of polyQ cytotoxicity through activation of daf-16 (member of FOXO family) [20]. These observations raised the possibility that caloric restriction (CR) as well as Sir2 activation may promote cell survival by inhibiting stressinduced apoptotic cell death and functions in a FOXO3-dependent manner, and may protect neurons expressing alleles associated with HD. Krainc and co-workers [21] in 2012 found that SIRT1-knockout mouse model of HD resulted in the exacerbation of brain pathology, whereas SIRT1 expression improved survival. SIRT1 had neuroprotective effects through the activation of TORC1 by promoting its dephosphorylation and its interaction with cAMP response element-binding protein that leads to the positive modulation of brain-derived neurotrophic factor activity. In contrast with the findings mentioned above, the potent SIRT1-selective inhibitor EX-527 (selisistat) is in phase II clinical trials for HD (clinical trials.gov identifier: NCT01521585), and only the outcome from the clinical trials will reveal the beneficial effects of SIRT1 inhibition in HD. The major beneficial effects of SIRT2 on HD depend on its hypomodulation, and SIRT2 inhibition leads to neuroprotection through reduced sterols biosynthesis [22]. After AD, Parkinson’s disease (PD) is the most common neurodegenerative disorder, characterized 2.3
by the accumulation of a-synuclein into inclusions Lewy bodies. The inhibition of SIRT2 by small molecules such as AGK2 or by knockout models results in the rescue of asynuclein mediated toxicity and promoted fewer and larger Lewy body-like inclusions [23]. 3.
Sirtuin modulators, patents 2012 -- 2014
Sirtuin inhibitors Starting from the reports available in literature in which SIRT1 and its positive modulation by resveratrol inhibit varicella zoster virus replication, [24], human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) [25] transactivation, and viral transgene expression of adenovirus in neuronal cells [26], Shenk et al. [27] patented the effects of the known sirtuin inhibitors EX-527, cambinol, tenovin-6, salermide, and of the SIRT1 activators resveratrol and the pyrroloquinoxaline CAY10602 (Figure 1) in virus production. First, the authors demonstrated that the prominent positive effect on human cytomegalovirus (HCMV) replication in infected MRC5 fibroblasts was mainly observed when mitochondrial SIRT3--5 were inhibited by short interfering RNA (siRNA), thus indicating for the first time that the activation of those isoforms could be useful targets for antiviral therapy. In the aforementioned cell line, the SIRT1 activators resveratrol (100 µM) and CAY10602 (25 µM) reduced HCMV yield under the limit of detection ( 1500 compounds were enzymatically assayed as potential SIRT1 activators [36-40] using a mass spectrometry (MS) assay based on the fluorophore-tagged 20-aminoacid peptide substrate (Ac-Glu-Glu-Lys(biotin)-Gly-GlnSer-Thr-Ser-Ser-His-Ser-Lys(Ac)-Nle-Ser-Thr-Glu-Gly--Lys (TAMRA)-Glu-Glu-NH2) derived from p53 [41], and/or on the tryptophan-containing Ac-Arg-His-Lys-Lys(Ac)-TrpNH2 substrate (SIRT1 tryptophan [TYP] MS assay) [42]. Among them, few 3-phenylquinazolinones (I) [36], 50 molecules bearing the 3-phenylimidazo[1,2-b]pyridazine and 3-phenyl [1,2,4]triazolo[4,3-b]pyridazine scaffolds (II) [37], 100 compounds with 2-phenylimidazo[1,2-b]pyridazine (III) and 2-phenylpyrazolo[1,5-a]pyrimidine (IV) structures obtained by a nice medicinal chemistry optimization of the previous 3-phenylimidazo[1,2-b]pyridazines [38], 1099 compounds bearing a 6-phenylimidazo[1,2-b]pyridazine (V, 1st set) or a 5-phenylpyrazolo[1,5-a]pyrimidine (VI, 2nd set) scaffold substituted at the C3 position with amide and reverse amide functions [39], and finally > 300 quinoline-, quinazoline-, and pyrido[3,2d]pyrimidine-based molecules (VII, VIII, and IX, respectively) [40] have been reported (Figure 3). While for the first series (I) the limited number of tested compounds and the lack of detailed EC1.5 and IC50 values do not allow a complete description of SAR, among compounds (II) 9 (Figure 3) gave the highest activation in both 6-carboxytetramethylrhodamine (TAMRA) and TYP assays showing EC1.5 < 1 µM. In the next two series, compound 1 (series III, Figure 3) carrying a ortho-trifluoromethyl substitution at the C2-phenyl ring and a 2-thiazolyl amide at the C8 position was one of the most potent as SIRT1 activator (EC1.5 < 1 µM) in the two assays, and compound 15 (series IV, Figure 3) bearing a 3-(2,3-dihydroxypropoxy)-2-pyridylamide, in addition to EC1.5 < 1 µM, showed also the maximum fold activation (> 350%). In the V and VI series (Figure 3), 77 out of 1099 compounds gained EC1.5 < 1 µM and fold activation ‡ 350%. Most of them carried a 6- (compounds V) or 5- (compounds VI) phenyl ring ortho-substituted with a trifluoromethyl group, a substituted pyridyl amide o retroamide at the C3 position, and occasionally methyl groups at C2, C7, and/or C8 positions. Finally, the
Expert Opin. Ther. Patents (2015) 25(1)
11
12
Expert Opin. Ther. Patents (2015) 25(1)
NCT01504854 NCT02123121
II II
HD: Huntington’s disease; NIAC-PKD1: Niacinamide in polycystic kidney disease.
NCT01768507
I
NCT01668836
I
Reresveratrol administered to healthy male subjects (REVAHS) Resveratrol for Alzheimer’s disease Resveratrol to enhance vitality and vigor in elders (REVIVE)
NCT00654667
II
NCT01765946
NCT01938521
I
IV
NCT01014117 NCT01262911 NCT01416376
I I I
Vascular system injuries, lipid metabolism disorders, endothelial dysfunction Insulin resistance, prediabetes, aging, inflammation Healthy subjects, heme oxygenase Alzheimer’s disease Mitochondrial function, physical function
Insulin resistance
Type 2 diabetes
Sepsis Sepsis Sepsis
Peripheral arterial disease
NCT02246660
I
Metabolic syndrome, obesity Diabetes mellitus, type 2 Diabetes mellitus, type 2
NCT01150955 NCT01018628
HD Type 2 diabetes
HD
HD
HD
Polycystic kidney disease
Disease(s)
I
I I
NCT01521585 NCT01677611
II I
Metformin and longevity genes in prediabetes
Potential beneficial effects of resveratrol A clinical study to assess the safety and pharmacokinetics of SRT2379 in normal healthy male volunteers A clinical trial to assess the safety of oral SRT2104 and its effects on vascular dysfunction in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus RESveratrol to improve Outcomes in oldeR pEople with PAD (the RESTORE trial) Effect of SRT2104 on endotoxin-induced inflammation Effect of SRT2379 on endotoxin-induced inflammation Effect of multiple dose levels of SRT2379 on endotoxininduced inflammation Effects of red grape cells (RGC) powder in type 2 diabetics (RGC-T2D) Mechanisms of metabolic regulation of resveratrol on humans with metabolic syndrome (RSV) Influence of caloric restriction and resveratrol in the sirtuin system in women and men aged 55 -- 65 years
NCT01485965
NCT01485952
I
I
NCT01521832
I
A open-label food effect study with SEN0014196 in subjects with HD A Phase II safety and tolerability study with SEN0014196 Effects of resveratrol in patients with type 2 diabetes
NCT02140814
II
Uncontrolled, open label, pilot and feasibility study of niacinamide in polycystic kidney disease (NIAC-PKD1) Escalating dose study in healthy volunteers with SEN0014196 An exploratory clinical trial in early stage HD patients with SEN0014196 (PADDINGTON)
Trial number
Phase
Study
Table 1. Sirtuin modulators in clinical trials for various diseases.
Dietary supplement: resveratrol Resveratrol, placebo Resveratrol 1000 mg/day, resveratrol 1500 mg/day, vegetable cellulose
Drug: resveratrol Behavioral: caloric restriction metformin, placebo
Dietary supplement: RGC, placebo placebo, resveratrol
placebo, SRT2104 SRT2379, placebo SRT2379, placebo
Resveratrol, placebo
SRT2104, placebo
SEN0014196, placebo Trans-resveratrol extract from Polygonum Cuspidatum, placebo Resveratrol, placebo SRT2379, placebo
SEN0014196 (Low Dose) SEN0014196 (High Dose), placebo SEN0014196
Dietary supplement: niacinamide SEN0014196
Drug(s)
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Completed Not yet recruiting
Completed
Completed
Recruiting
Withdrawn
Recruiting
Completed Completed Completed
Not yet recruiting
Completed
Completed Completed
Completed Completed
Completed
Completed
Completed
Recruiting
Status
P. Mellini et al.
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Sirtuin modulators: an updated patent review (2012 -- 2014)
highest SIRT1 activation (TAMRA-based assay) in compounds of series VII--IX has been reached by the insertion of a nitrogen-containing heterocycle at the C8-amide (for VII and VIII) or C4-retroamide (for IX) function, and a fluoromethyl or fluoromethoxy substituent at the meta position of the C2 (for VII and VIII) or C6 (for IX) phenyl ring (Figure 3). Unfortunately, because of the absence of an exact EC1.5 value, it is not possible to identify a lead compound. Next, with the aim to provide novel heterocyclic compounds acting by mimicking the nicotinamide portion of NAD+, Larsen et al. [43] described a small array of pyridine2,5-dicarboxamide and pyrrol-2,4-dicarboxamide derivatives as SIRT1 modulators. Selected compounds were assayed using a modified CISBIO HTRF SIRT1 assay kit, in which without NAD+ they showed the ability to induce substrate deacetylation. Compounds 1--3 gave an activation AC50 of 3.3 µM, 10 µM, and 31.6 µM, respectively, while compound 4 with the pyrrol-2,4-dicarboxamide moiety was found to be an SIRT1 inhibitor with an IC50 of 0.5 µM (AC50 and IC50 were calculated from LogC value at 50% fluorescence) (Figure 4). 4.
Expert opinion
From their discovery, sirtuins have been retained different from the other ‘classical’ HDACs, so that it seems to be convenient to inhibit some isoforms and/or to activate others [44]. In other cases, the single isoform may present both a dark and bright side, so that it should be inhibited or activated depending on the cell type setting and environment. In fact, as sensors of the metabolic state of the cells, sirtuins play crucial roles in metabolism, aging, cardiovascular and neurological functions, as well as in cancer initiation and development. Due to their capability to work with acetylated histone and (mainly) non-histone substrates, including transcription factors and cytoskeleton proteins, sirtuins can exert transcriptional and non-transcriptional functions linked to the physiology and/or pathology of mammals. SIRTs play a controversial role in cancer, for which their role as either tumor promoter or tumor suppressor depends on the cell context and status, the cellular environment, and the active pathways involved, in 2012 -- 2014 patents regarding the discovery or the use of SIRT inhibitors in various diseases have been released. Known SIRT inhibitors were reported as able to block virus infections (HCMV, influenza A virus, adenovirus Ad5), or to increase the skeletal muscle growth in mammals.
Among new molecules, some pPHOS displayed high antiproliferative effects in a panel of cancer cells, and some thieno [3,2-d]pyrimidine-6-carboxamides were recently disclosed as pan-SIRT1/2/3 inhibitors potent at nanomolar level. Unfortunately, no biological data have been reported for these last compounds. On the other hand, a great number of new molecules as SIRT activators have been described. Most of these compounds were identified through the use of fluorophoretagged TAMRA and/or tryptophan-containing (TYP) substrates, and did not show SIRT activation with other natural substrates [45,46], thus their real direct sirtuin activation is controversial [1]. Actually, there is an open debate on the mechanism of activation of SIRT1 by resveratrol and other sirtuinactivating compounds (STACs): i) an indirect way, involving the phosphodiesterase/AMPK pathway; and ii) a direct way, suggesting a physical interaction with the enzyme at an allosteric binding site, after the discovery of SIRT1 mutations at the E230 residue (E230K or E230A) which abated the STACs’ activation capability [42]. Anyway, either direct or indirect SIRT activation can lead to beneficial effects in neurodegenerative diseases (such as AD, HD, and PD), metabolic disorders (such as obesity and type 2 diabetes with their complications), inflammation, vascular system injuries, wound healing and endothelial dysfunctions. A number of clinical trials are reported for nicotinamide, a SIRT inhibitor, as a dietary supplier for the treatment of polycystic kidney disease, and for EX-527 (selisistat, SEN0014196), the SIRT1 -selective inhibitor, for the therapy of HD (Table 1). A greater number of clinical trials involve resveratrol and other SIRT activators (including one with metformin, a hypoglycemic agent able to increase SIRT1 protein expression [47], Table 1), so it is possible that in the foreseeable future one or more SIRT inhibitors and/or activators will reach the approval for the treatment of some of the above cited pathologies.
Declaration of interest The authors were supported by the Italian Ministry of Health funds: FIRB RBFR10ZJQT, RF-2010-2318330, Progetto Ateneo Sapienza 2013, FP7 Projects BLUEPRINT/ 282510 and A-ParaDDisE/602080. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Blum C, Springer S, Vu C. Substituted Bicyclic Aza-Heterocycles and Analogues as Sirtuin Modulators. WO2013059589A1; 2013 Blum C, Disch J, Springer S. Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators. WO2013059594A1; 2013 Casaubon R, Narayan R, Oalmann C, et al. Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators. WO2013059587A1; 2013
42.
.
43.
Hubbard BP, Gomes AP, Dai H, et al. Evidence for a common mechanism of sirt1 regulation by allosteric activators. Science 2013;339:1216-19 The last output in the field of SIRT1 activators. Larsen BD, Andersen S, Larsen MS. Novel heterocyclic compounds useful in sirtuin binding and modulation. WO2013090369A1; 2013
44.
Vu CB, Disch JS, Springer SK, et al. Quinolines and related analogs as sirtuin modulators. US8685970B2; 2014
Dillin A, Kelly JW. Medicine. The yinyang of sirtuins. Science 2007;317:461-2
45.
Milne JC, Lambert PD, Schenk S, et al. Small molecule activators of sirt1 as therapeutics for the treatment of type 2 diabetes. Nature 2007;450:12-716 The discovery of SRT1720, the debated SIRT1 activator.
Pacholec M, Bleasdale JE, Chrunyk B, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 2010;285:8340-51
46.
Dai H, Kustigian L, Carney D, et al. SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and
Expert Opin. Ther. Patents (2015) 25(1)
activator. J Biol Chem 2010;285:32695-703 47.
Arunachalam G, Samuel SM, Marei I, et al. Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. Br J Pharmacol 2014;171:523-35
Affiliation Paolo Mellini1, Sergio Valente1 & Antonello Mai†1,2 † Author for correspondence 1 Sapienza Universita di Roma, Dipartimento di Chimica e Tecnologie del Farmaco, P.le A. Moro 5, 00185 Rome, Italy 2 Department of Drug Chemistry and Technologies, Sapienza Universita di Roma, Istituto Pasteur-Fondazione Cenci Bolognetti, P.le A. Moro 5, 00185 Rome, Italy Tel: +3906 49913392; Fax: +3906 49693268; E-mail: [email protected]
15
Sirtuin modulators: an updated patent review (2012 -- 2014) Paolo Mellini, Sergio Valente & Antonello Mai† 2.
SIRT1--7 and their biological relevance in diseases: a brief update from literature
3.
Sirtuin modulators, patents
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Chulalongkorn University on 01/03/15 For personal use only.
2012 -- 2014 4.
Expert opinion
†
Department of Drug Chemistry and Technologies, Sapienza Universit a di Roma, Istituto PasteurFondazione Cenci Bolognetti, Rome, Italy
Introduction: Since 2000 sirtuins (SIRT1--7) have gained growing attention for their connections with many biological processes such as cellular metabolism regulation, neuroprotection, apoptosis, inflammation, and cancer progression. In particular, SIRT1 has been the most studied isoform, not only for its role during caloric restriction but also as target in prevention of aging-related diseases. SIRT inhibition can be useful for treating cancer, HIV infection or muscular diseases, SIRT activation can exert positive effects in aging-related disorders such as metabolism, cardiovascular, and neurodegenerative diseases. Areas covered: This review includes the patents about sirtuin modulation released during the 2012 -- 2014 period, and covers the potential therapeutic uses of known sirtuin modulators as well as new related small molecules in various disease contexts. Expert opinion: The effective role of sirtuins in cancer is still controversial, because some of them seem to have tumor-promoter as well as tumorsuppressor properties. Thus, few patents describing SIRT inhibitors have been found in 2012 -- 2014 period. Despite the still active debate on their role as direct or indirect activators of SIRT1, sirtuin-activating compounds are actually subjected to intense research for the ability to treat neurodegenerative diseases, metabolic disorders, inflammation, vascular system injuries, wound healing and endothelial dysfunctions. A great number of clinical trials are reported with either SIRT inhibitors or activators, thus it is possible that in the foreseeable future one or more of them will enter in the clinical arena. Keywords: diabetes, epigenetics, inflammation, obesity, sirtuins, small molecule activators Expert Opin. Ther. Patents (2015) 25(1):5-15
In this review, after an introduction on sirtuins and their biological roles in diseases, we examined all the patents reported in literature in the years 2012 -- 2014 describing new therapeutic applications as well as novel small molecules related to sirtuin modulators. Bibliographic research was carried out using Espacenet and SciFinder. Only patents published in English have been considered. 1.
Introduction
Sirtuins belong to the class III histone deacetylases (HDACs) and are NAD+-dependent enzymes [1]. From yeast to humans, they contain a highly conserved catalytic core domain formed by 275 amino acids, and N,C-terminal extensions variable in length and sequence that can (1) affect the binding with interacting partners, (2) mediate interactions with other sirtuin forms, and (3) direct cellular localization. In mammals there are seven sirtuin isoforms (SIRT1--7) able to catalyze specific lysine substrate deacetylation/deacylation [1]. Among them, SIRT4 and SIRT6 possess mainly NAD+-dependent mono-ADP-ribosyltransferase activity, SIRT5 has been reported to have potent demalonylase/desuccinylase activity [2], and other deacylation reactions can be catalyzed by SIRT6 [3]. The seven SIRT1--7 isoforms are differently located 10.1517/13543776.2014.982532 © 2015 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. .
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.
A key introduction through a novel update from literature that shows each promising therapeutic application of sirtuin modulators. The patents’ production in the field of sirtuin modulators in the years 2012 -- 2014 was examined. The activity of known dual SIRT1/2 inhibitors and SIRT1 activators was evaluated and found beneficial not only in reducing virus production but also as promising strategy for metabolic as well as neurodegenerative diseases. A large number of compounds bearing different bicyclic moieties including phenylquinazolinones, phenylimidazo [1,2-b]pyridazines, phenyl-[1,2,4]triazolo[4,3-b] pyridazines, phenylpyrazolo[1,5-a]pyrimidines, quinolines, quinazolines and pyrido[3,2-d]pyrimidines were described as SIRT1 activators. Despite the debate on their direct or indirect mechanism of SIRT activation is still open, their phenotypic effects on positive regulation in metabolism and cardiovascular diseases and in neurodegeneration seem to be undoubted.
This box summarizes key points contained in the article.
within cellular compartments depending on cell type, stress conditions and interaction with other proteins [4]. SIRT1, SIRT6, and SIRT7 are typically nuclear enzymes, with SIRT7 preferentially located into nucleolus. SIRT1 can be also found in cytoplasm, where SIRT2 is predominantly located. SIRT3, -4, and -5 are localized in the mitochondria, but SIRT3 localization is still debated because of its potential translocation to the nucleus under cellular stress conditions [1]. For deacetylation, sirtuins can accept histone as well as a number of non-histone substrates [5], and it can explain the wide biological processes in which these enzymes are involved, ranging from metabolic, cardiovascular and neurodegenerative diseases to cancer development and progression.
SIRT1--7 and their biological relevance in diseases: a brief update from literature
2.
Sirtuins and metabolic functions SIRT1 is directly involved on metabolic pathways such as lipogenesis, stimulation of fatty acid b-oxidation, and gluconeogenesis. Its overexpression is thought to be beneficial and generates phenotypes in mice similar to calorie restriction conditions. All the major mitochondrial processes including the Krebs cycle, the fatty acid metabolism, the antioxidant response, the amino acid catabolism, and so on, are regulated by the balance of N"-lysine acetylation/deacetylation. SIRT3, the most well-characterized mitochondrial sirtuin, shows a robust deacetylase activity. SIRT3 exists as a nuclear full length form FL-SIRT3 that is processed as a result of cellular stress to the short mitochondrial form. Nuclear FL-SIRT3 [6] exhibits deacetylase activity coherently with the fact that SIRT3 regulates the expression and activity of nuclear genes 2.1
6
such as peroxisome proliferator-activated receptor-g coactivator-1a and manganese superoxide dismutase, and modulates forkhead box O3 (FOXO3a) by direct deacetylation. SIRT3 may regulate cellular energy status both at transcriptional level in the nucleus and by posttranscriptional mechanisms in mitochondria, and its expression is higher in metabolically active tissues including brain, liver, heart, brown adipose tissue and skeletal muscle [7]. SIRT4 is located in the mitochondrial matrix and exhibits prevalently ADP-ribosylase and a weak deacetylase activity. Little is known about the physiological relevance of SIRT4 and its role in metabolism. Recently, Haigis and coworkers [8] showed that SIRT4 promoted lipid synthesis and inhibition of fatty acid oxidation by deacetylation of malonyl CoA decarboxylase, an enzyme that produces acetyl-CoA from malonyl-CoA. SIRT5 has weak deacetylase activity, one of the substrate reported to be deacetylated being CPS1 (carbamoyl phosphatase 1), a key enzyme of the urea cycle. Deacetylation of CPS1 by SIRT5 was found to improve ammonia detoxification. Recently, Lin and co-workers [2] showed that SIRT5 has potent demalonylation and desuccinylation enzymatic activity, and that CPS1, isocitrate dehydrogenase 2, glutamate dehydrogenase and 3-hydroxy-3-methylglutaryl-CoA synthase 2 are subjected to these post-translational modifications. The involvement of SIRT5 in metabolic pathways needs to further investigation. The first indication of the connection between SIRT6 and metabolism was provided by Mostoslavsky et al. [9] who showed that SIRT6-deficient mice had a loss of subcutaneous fat, lymphopenia and acute hypoglycemia. Sirtuins and cancer Among the sirtuin family, the involvement of SIRT1 in cancer is the most studied and it is decisively controversial and contradictory. SIRT1 normally protects cells from oncogenic transformation, but on the other side its enzymatic activity can promote cancer growth by deacetylation/inactivation of proapoptotic factors [10,11]. SIRT1 is overexpressed in different kinds of tumors such as prostate, breast, lung, hepatocellular, neuroblastoma, lymphoma and leukemia, colorectal, pancreatic, and gastric cancers. During tumorigenesis, SIRT2 also can function as both tumor promoter and suppressor, this behavior seeming to be dependent on the cellular context. The expression of SIRT2 has been found downregulated in several cancers (such as gliomas, breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, and esophageal adenocarcinoma), and elevated in others (such as neuroblastoma, pancreatic cancer, and acute myeloid leukemia) [13,14]. Several studies highlight a prosurvival role for SIRT3 in both normal and cancer cells, in which SIRT3 seems to control proliferative and survival pathways. Recently, SIRT3 has been found overexpressed in head and neck squamous cell carcinoma, where it regulates reactive oxygen species to a level able to maintain a proliferative and aggressive cell phenotype and to prevent apoptosis [15]. A proapoptotic role has also been proposed, but this dualism tumor promoter/suppressor showed by SIRT3 needs further 2.2
Expert Opin. Ther. Patents (2015) 25(1)
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Sirtuin modulators: an updated patent review (2012 -- 2014)
investigations. Growing evidences show that SIRT6 is a tumor suppressor protein [16]. SIRT6 involvement in cancer progression is mainly its ability to regulate metabolic functions. Tumor cells need to readjust their energy metabolism to fuel cell growth and division, and glucose metabolism is the best known example of metabolic reprogramming in cancer cells. SIRT6 regulates aerobic glycolysis in cancer cells, and SIRT6-deficient cells develop cancer regardless of oncogene activation [17]. The nucleolar SIRT7 exists also as a cytoplasmic form, and has been supported to play a crucial role in oxidative and genotoxic stress response. SIRT7 is more abundant in highly proliferative than in lowly proliferative tissues, and a role for SIRT7 as activator of proliferation has been proposed. SIRT7 was reported to be upregulated in breast and thyroid cancers, and the consequent H3K18 hypoacetylation was considered a marker of malignancy [18]. Sirtuins and neurodegenerative disease Alzheimer’s disease (AD) is one of the most common and devastating age-related neurodegenerative diseases. In in vitro models the expression of SIRT1 protects microglia cells through the inhibition of nuclear factor kappa B (NF-kB) signaling by deacetylation at Lys310 of its RelA/p65 subunit [19]. AD in the APPswe/PS1dE9 mouse model (Ab plaque formation and learning and memory deficits) was mitigated by SIRT1 overexpression and exacerbated in mice with SIRT1knocked out in the brain. Huntington’s disease (HD) is a neurodegenerative genetic polyglutamine (polyQ) disorder. The disease is caused by an autosomal dominant mutation of two copies of a gene called Huntingtin, which gradually damages cells in the brain. In a C. elegans model for HD, the promotion of Sir2 activity was found protective against the early phases of polyQ cytotoxicity through activation of daf-16 (member of FOXO family) [20]. These observations raised the possibility that caloric restriction (CR) as well as Sir2 activation may promote cell survival by inhibiting stressinduced apoptotic cell death and functions in a FOXO3-dependent manner, and may protect neurons expressing alleles associated with HD. Krainc and co-workers [21] in 2012 found that SIRT1-knockout mouse model of HD resulted in the exacerbation of brain pathology, whereas SIRT1 expression improved survival. SIRT1 had neuroprotective effects through the activation of TORC1 by promoting its dephosphorylation and its interaction with cAMP response element-binding protein that leads to the positive modulation of brain-derived neurotrophic factor activity. In contrast with the findings mentioned above, the potent SIRT1-selective inhibitor EX-527 (selisistat) is in phase II clinical trials for HD (clinical trials.gov identifier: NCT01521585), and only the outcome from the clinical trials will reveal the beneficial effects of SIRT1 inhibition in HD. The major beneficial effects of SIRT2 on HD depend on its hypomodulation, and SIRT2 inhibition leads to neuroprotection through reduced sterols biosynthesis [22]. After AD, Parkinson’s disease (PD) is the most common neurodegenerative disorder, characterized 2.3
by the accumulation of a-synuclein into inclusions Lewy bodies. The inhibition of SIRT2 by small molecules such as AGK2 or by knockout models results in the rescue of asynuclein mediated toxicity and promoted fewer and larger Lewy body-like inclusions [23]. 3.
Sirtuin modulators, patents 2012 -- 2014
Sirtuin inhibitors Starting from the reports available in literature in which SIRT1 and its positive modulation by resveratrol inhibit varicella zoster virus replication, [24], human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) [25] transactivation, and viral transgene expression of adenovirus in neuronal cells [26], Shenk et al. [27] patented the effects of the known sirtuin inhibitors EX-527, cambinol, tenovin-6, salermide, and of the SIRT1 activators resveratrol and the pyrroloquinoxaline CAY10602 (Figure 1) in virus production. First, the authors demonstrated that the prominent positive effect on human cytomegalovirus (HCMV) replication in infected MRC5 fibroblasts was mainly observed when mitochondrial SIRT3--5 were inhibited by short interfering RNA (siRNA), thus indicating for the first time that the activation of those isoforms could be useful targets for antiviral therapy. In the aforementioned cell line, the SIRT1 activators resveratrol (100 µM) and CAY10602 (25 µM) reduced HCMV yield under the limit of detection ( 1500 compounds were enzymatically assayed as potential SIRT1 activators [36-40] using a mass spectrometry (MS) assay based on the fluorophore-tagged 20-aminoacid peptide substrate (Ac-Glu-Glu-Lys(biotin)-Gly-GlnSer-Thr-Ser-Ser-His-Ser-Lys(Ac)-Nle-Ser-Thr-Glu-Gly--Lys (TAMRA)-Glu-Glu-NH2) derived from p53 [41], and/or on the tryptophan-containing Ac-Arg-His-Lys-Lys(Ac)-TrpNH2 substrate (SIRT1 tryptophan [TYP] MS assay) [42]. Among them, few 3-phenylquinazolinones (I) [36], 50 molecules bearing the 3-phenylimidazo[1,2-b]pyridazine and 3-phenyl [1,2,4]triazolo[4,3-b]pyridazine scaffolds (II) [37], 100 compounds with 2-phenylimidazo[1,2-b]pyridazine (III) and 2-phenylpyrazolo[1,5-a]pyrimidine (IV) structures obtained by a nice medicinal chemistry optimization of the previous 3-phenylimidazo[1,2-b]pyridazines [38], 1099 compounds bearing a 6-phenylimidazo[1,2-b]pyridazine (V, 1st set) or a 5-phenylpyrazolo[1,5-a]pyrimidine (VI, 2nd set) scaffold substituted at the C3 position with amide and reverse amide functions [39], and finally > 300 quinoline-, quinazoline-, and pyrido[3,2d]pyrimidine-based molecules (VII, VIII, and IX, respectively) [40] have been reported (Figure 3). While for the first series (I) the limited number of tested compounds and the lack of detailed EC1.5 and IC50 values do not allow a complete description of SAR, among compounds (II) 9 (Figure 3) gave the highest activation in both 6-carboxytetramethylrhodamine (TAMRA) and TYP assays showing EC1.5 < 1 µM. In the next two series, compound 1 (series III, Figure 3) carrying a ortho-trifluoromethyl substitution at the C2-phenyl ring and a 2-thiazolyl amide at the C8 position was one of the most potent as SIRT1 activator (EC1.5 < 1 µM) in the two assays, and compound 15 (series IV, Figure 3) bearing a 3-(2,3-dihydroxypropoxy)-2-pyridylamide, in addition to EC1.5 < 1 µM, showed also the maximum fold activation (> 350%). In the V and VI series (Figure 3), 77 out of 1099 compounds gained EC1.5 < 1 µM and fold activation ‡ 350%. Most of them carried a 6- (compounds V) or 5- (compounds VI) phenyl ring ortho-substituted with a trifluoromethyl group, a substituted pyridyl amide o retroamide at the C3 position, and occasionally methyl groups at C2, C7, and/or C8 positions. Finally, the
Expert Opin. Ther. Patents (2015) 25(1)
11
12
Expert Opin. Ther. Patents (2015) 25(1)
NCT01504854 NCT02123121
II II
HD: Huntington’s disease; NIAC-PKD1: Niacinamide in polycystic kidney disease.
NCT01768507
I
NCT01668836
I
Reresveratrol administered to healthy male subjects (REVAHS) Resveratrol for Alzheimer’s disease Resveratrol to enhance vitality and vigor in elders (REVIVE)
NCT00654667
II
NCT01765946
NCT01938521
I
IV
NCT01014117 NCT01262911 NCT01416376
I I I
Vascular system injuries, lipid metabolism disorders, endothelial dysfunction Insulin resistance, prediabetes, aging, inflammation Healthy subjects, heme oxygenase Alzheimer’s disease Mitochondrial function, physical function
Insulin resistance
Type 2 diabetes
Sepsis Sepsis Sepsis
Peripheral arterial disease
NCT02246660
I
Metabolic syndrome, obesity Diabetes mellitus, type 2 Diabetes mellitus, type 2
NCT01150955 NCT01018628
HD Type 2 diabetes
HD
HD
HD
Polycystic kidney disease
Disease(s)
I
I I
NCT01521585 NCT01677611
II I
Metformin and longevity genes in prediabetes
Potential beneficial effects of resveratrol A clinical study to assess the safety and pharmacokinetics of SRT2379 in normal healthy male volunteers A clinical trial to assess the safety of oral SRT2104 and its effects on vascular dysfunction in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus RESveratrol to improve Outcomes in oldeR pEople with PAD (the RESTORE trial) Effect of SRT2104 on endotoxin-induced inflammation Effect of SRT2379 on endotoxin-induced inflammation Effect of multiple dose levels of SRT2379 on endotoxininduced inflammation Effects of red grape cells (RGC) powder in type 2 diabetics (RGC-T2D) Mechanisms of metabolic regulation of resveratrol on humans with metabolic syndrome (RSV) Influence of caloric restriction and resveratrol in the sirtuin system in women and men aged 55 -- 65 years
NCT01485965
NCT01485952
I
I
NCT01521832
I
A open-label food effect study with SEN0014196 in subjects with HD A Phase II safety and tolerability study with SEN0014196 Effects of resveratrol in patients with type 2 diabetes
NCT02140814
II
Uncontrolled, open label, pilot and feasibility study of niacinamide in polycystic kidney disease (NIAC-PKD1) Escalating dose study in healthy volunteers with SEN0014196 An exploratory clinical trial in early stage HD patients with SEN0014196 (PADDINGTON)
Trial number
Phase
Study
Table 1. Sirtuin modulators in clinical trials for various diseases.
Dietary supplement: resveratrol Resveratrol, placebo Resveratrol 1000 mg/day, resveratrol 1500 mg/day, vegetable cellulose
Drug: resveratrol Behavioral: caloric restriction metformin, placebo
Dietary supplement: RGC, placebo placebo, resveratrol
placebo, SRT2104 SRT2379, placebo SRT2379, placebo
Resveratrol, placebo
SRT2104, placebo
SEN0014196, placebo Trans-resveratrol extract from Polygonum Cuspidatum, placebo Resveratrol, placebo SRT2379, placebo
SEN0014196 (Low Dose) SEN0014196 (High Dose), placebo SEN0014196
Dietary supplement: niacinamide SEN0014196
Drug(s)
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Completed Not yet recruiting
Completed
Completed
Recruiting
Withdrawn
Recruiting
Completed Completed Completed
Not yet recruiting
Completed
Completed Completed
Completed Completed
Completed
Completed
Completed
Recruiting
Status
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Sirtuin modulators: an updated patent review (2012 -- 2014)
highest SIRT1 activation (TAMRA-based assay) in compounds of series VII--IX has been reached by the insertion of a nitrogen-containing heterocycle at the C8-amide (for VII and VIII) or C4-retroamide (for IX) function, and a fluoromethyl or fluoromethoxy substituent at the meta position of the C2 (for VII and VIII) or C6 (for IX) phenyl ring (Figure 3). Unfortunately, because of the absence of an exact EC1.5 value, it is not possible to identify a lead compound. Next, with the aim to provide novel heterocyclic compounds acting by mimicking the nicotinamide portion of NAD+, Larsen et al. [43] described a small array of pyridine2,5-dicarboxamide and pyrrol-2,4-dicarboxamide derivatives as SIRT1 modulators. Selected compounds were assayed using a modified CISBIO HTRF SIRT1 assay kit, in which without NAD+ they showed the ability to induce substrate deacetylation. Compounds 1--3 gave an activation AC50 of 3.3 µM, 10 µM, and 31.6 µM, respectively, while compound 4 with the pyrrol-2,4-dicarboxamide moiety was found to be an SIRT1 inhibitor with an IC50 of 0.5 µM (AC50 and IC50 were calculated from LogC value at 50% fluorescence) (Figure 4). 4.
Expert opinion
From their discovery, sirtuins have been retained different from the other ‘classical’ HDACs, so that it seems to be convenient to inhibit some isoforms and/or to activate others [44]. In other cases, the single isoform may present both a dark and bright side, so that it should be inhibited or activated depending on the cell type setting and environment. In fact, as sensors of the metabolic state of the cells, sirtuins play crucial roles in metabolism, aging, cardiovascular and neurological functions, as well as in cancer initiation and development. Due to their capability to work with acetylated histone and (mainly) non-histone substrates, including transcription factors and cytoskeleton proteins, sirtuins can exert transcriptional and non-transcriptional functions linked to the physiology and/or pathology of mammals. SIRTs play a controversial role in cancer, for which their role as either tumor promoter or tumor suppressor depends on the cell context and status, the cellular environment, and the active pathways involved, in 2012 -- 2014 patents regarding the discovery or the use of SIRT inhibitors in various diseases have been released. Known SIRT inhibitors were reported as able to block virus infections (HCMV, influenza A virus, adenovirus Ad5), or to increase the skeletal muscle growth in mammals.
Among new molecules, some pPHOS displayed high antiproliferative effects in a panel of cancer cells, and some thieno [3,2-d]pyrimidine-6-carboxamides were recently disclosed as pan-SIRT1/2/3 inhibitors potent at nanomolar level. Unfortunately, no biological data have been reported for these last compounds. On the other hand, a great number of new molecules as SIRT activators have been described. Most of these compounds were identified through the use of fluorophoretagged TAMRA and/or tryptophan-containing (TYP) substrates, and did not show SIRT activation with other natural substrates [45,46], thus their real direct sirtuin activation is controversial [1]. Actually, there is an open debate on the mechanism of activation of SIRT1 by resveratrol and other sirtuinactivating compounds (STACs): i) an indirect way, involving the phosphodiesterase/AMPK pathway; and ii) a direct way, suggesting a physical interaction with the enzyme at an allosteric binding site, after the discovery of SIRT1 mutations at the E230 residue (E230K or E230A) which abated the STACs’ activation capability [42]. Anyway, either direct or indirect SIRT activation can lead to beneficial effects in neurodegenerative diseases (such as AD, HD, and PD), metabolic disorders (such as obesity and type 2 diabetes with their complications), inflammation, vascular system injuries, wound healing and endothelial dysfunctions. A number of clinical trials are reported for nicotinamide, a SIRT inhibitor, as a dietary supplier for the treatment of polycystic kidney disease, and for EX-527 (selisistat, SEN0014196), the SIRT1 -selective inhibitor, for the therapy of HD (Table 1). A greater number of clinical trials involve resveratrol and other SIRT activators (including one with metformin, a hypoglycemic agent able to increase SIRT1 protein expression [47], Table 1), so it is possible that in the foreseeable future one or more SIRT inhibitors and/or activators will reach the approval for the treatment of some of the above cited pathologies.
Declaration of interest The authors were supported by the Italian Ministry of Health funds: FIRB RBFR10ZJQT, RF-2010-2318330, Progetto Ateneo Sapienza 2013, FP7 Projects BLUEPRINT/ 282510 and A-ParaDDisE/602080. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation Paolo Mellini1, Sergio Valente1 & Antonello Mai†1,2 † Author for correspondence 1 Sapienza Universita di Roma, Dipartimento di Chimica e Tecnologie del Farmaco, P.le A. Moro 5, 00185 Rome, Italy 2 Department of Drug Chemistry and Technologies, Sapienza Universita di Roma, Istituto Pasteur-Fondazione Cenci Bolognetti, P.le A. Moro 5, 00185 Rome, Italy Tel: +3906 49913392; Fax: +3906 49693268; E-mail: [email protected]
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