Class I HDAC Inhibitors: Potential New Epigenetic ... - ACS Publications

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Class I HDAC Inhibitors: Potential New Epigenetic Therapeutics for Alcohol Use Disorder (AUD) Erika Bourguet,*,†,⊥ Katarzyna Ozdarska,†,‡ Gautier Moroy,§ Jérôme Jeanblanc,∥,⊥ and Mickael̈ Naassila*,∥,⊥ †

Institut de Chimie Moléculaire de Reims, UMR 7312-CNRS, UFR Pharmacie, Université de Reims Champagne−Ardenne, 51 rue Cognacq-Jay, 51096 Reims Cedex, France ‡ Department of Bioanalysis and Drugs Analysis, Medical University of Warsaw, S. Banacha 1, 02-097 Warsaw, Poland § Sorbonne Paris Cité, Molécules Thérapeutiques In Silico (MTi), INSERM UMR-S 973, Université Paris Diderot, 35 rue Hélène Brion, 75013 Paris, France ∥ INSERM ERi 24, Groupe de Recherche sur l’Alcool et les Pharmacodépendances (GRAP), Université de Picardie Jules Verne, C.U.R.S. (Centre Universitaire de Recherche en Santé), Chemin du Thil, 80000 Amiens, France ⊥ Structure Fédérative de Recherche-Champagne Ardenne Picardie Santé (SFR-CAP Santé), 51095 Reims Cedex, France

ABSTRACT: Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/ deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.

1. INTRODUCTION

anxiety, and craving, which promote relapse after periods of short or protracted abstinence. Alcohol can reduce dysphoria and anxiety, thus leading to self-medication.1 Several discoveries have implicated a direct involvement of altered gene expression in the regulation of neuronal functions underlying AUD. On the one hand, the long-term neuroadaptations underlying AUD are mediated through persistent changes in gene expression that require chromatin remodeling. Epigenetic modifications, such as histone acetylation and deacetylation, regulate gene expression by altering the conformation of chromatin and control the accessibility of DNA to transcriptional machinery. The term “epigenetic” refers to the features that change gene

In recent years, great progress has been made in understanding the neurobiological mechanisms underlying the development of alcohol use disorder (AUD) (abuse and addiction). Vulnerability to developing AUD depends on complex interactions between genetic and epigenetic factors. Alcohol addiction is a chronic disease characterized by (1) loss of control over alcohol intake, (2) compulsive use of alcohol, (3) crystallization of behavior around drug-taking, (4) social and professional problems, (5) cravings, and (6) physical signs such as tolerance and withdrawal symptoms. There is a pressing need to identify the molecular pathways leading to AUD and to find new, effective treatments. One of the main problems associated with alcohol addiction is its “dark side” characterized by withdrawal, dysphoria, stress, © 2017 American Chemical Society

Received: January 22, 2017 Published: August 3, 2017 1745

DOI: 10.1021/acs.jmedchem.7b00115 J. Med. Chem. 2018, 61, 1745−1766

Journal of Medicinal Chemistry

Perspective

for disease, disability and death throughout the world, and is a causal factor in more than 200 diseases and injury conditions.5 Its consumption is the highest in Europe and reaches 8.84 L of pure ethanol per adult a year. It is considered the cause of 3.8% of deaths each year (2.3 million people worldwide) and 4.5% of disability adjusted life-years. In 2010, the number of alcohol-dependent people was estimated to be 3.4% among people 18−64 years of age (5.2% in men and 1.7% in women)6 in Europe. People drinking more than 12 L of pure alcohol a year, constituting barely 7.3% of all consumers, consumed 46.1% of the total amount of alcohol. This startling concentration of alcohol intake in such a small proportion of the population leads to severe health damage and social problems. At-risk alcohol intake is the most common risky behavior among adolescents (early use can lead to AUD, comorbid psychopathology and anxiety in adulthood).7 Actually, 40% of adolescent drug-related visits to the emergency department are due to alcohol intake and alarmingly contribute to a large number of deaths in people between the ages of 15 and 29. Brain development and synaptic plasticity are important during adolescence. Brain maturation leads to a normal behavioral state via epigenetic mechanisms, and perturbation of this process by ethanol exposure can disrupt normal epigenetic programming. 2.2. Status of Current Treatments. Although available treatments have shown effectiveness in reducing alcohol consumption and maintaining abstinence, 40−70% of patients still relapse to drinking within a year following treatment,8 and 90% and 95% still relapse within 4 and 8 years, respectively.9,10 Pharmacotherapies against AUD aim at either reducing alcohol intake or maintaining abstinence. Reduction of alcohol intake may represent the first step toward abstinence because approximately 50% of patients declare that they do not wish to become abstinent, thus partially explaining why fewer than 10% of patients seek treatment for their AUD, which is the so-called “treatment gap”.11 Therefore, it is important to remember when developing new treatments that new molecules must be effective in either reducing alcohol intake, maintaining abstinence, or both. Currently, three drugs are used to maintain abstinence, naltrexone (1), acamprosate (3), and disulfiram (4), while two other drugs are used to reduce alcohol intake, nalmefene (2) and baclofen (5) (Figure 1).12 In addition, in Italy and Austria, sodium oxybate is also approved for both the treatment of alcohol withdrawal syndrome and the prevention of alcohol relapse.

expression without altering the DNA sequence. On the other hand, alcohol inhibits histone deacetylase (HDAC) activity, and recent studies have demonstrated that inhibitors of HDAC (HDACIs) are effective in reducing excessive intake and relapse in alcohol-dependent animals. This suggests that HDACIs should be promising as a new therapeutic option in the treatment of AUD.2,3 With this Perspective, we review the literature reporting the progress that has been made on the design and discovery of HDACIs and, more specifically, on those that are selective for class I HDACs. Different isoforms of HDAC have been described in humans (see 3.1 for details), and greater selectivity could provide a therapeutic advantage for the tolerability and efficiency of new selective inhibitors. Future efforts to better define the structure and functional distribution of HDAC enzymes in the brain and the development of modeling approaches should be the basis for the discovery of novel, effective inhibitors.

2. ALCOHOL USE DISORDER 2.1. Generalities. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)4 definition, alcohol dependence is a complex disease in which alcohol consumption has become predominant over other actions that were previously important to a patient. The main symptoms of AUD are craving for alcohol, loss of control over intake, and compulsive use. In 2013, the terminology changed, and alcohol dependence was classified together with alcohol abuse by the DSM-5 into one disorder called AUD. The recognition of AUD is based on the presence of at least two of the following criteria simultaneously within one year: • Drinking in larger amounts or over a longer period than intended • Persistent desire or one or more unsuccessful efforts to cut down or control drinking • Extensive time spent engaging in activities aiming to get or use alcohol or recover from its effects • Craving (subjective experience of wanting to drink alcohol) • Recurrent use of alcohol resulting in a failure to fulfill major obligations at work, school, or home • Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol • Important social, occupational, or recreational activities forfeited or reduced because of drinking • Recurrent alcohol use in physically hazardous situations • Continued drinking despite knowledge of having a persistent or recurrent physical or psychological problem likely caused or exacerbated by drinking • Tolerance to the effects of alcohol (i.e., the need for markedly increased amounts of alcohol to achieve intoxication or the desired effects, or markedly diminished effects with continued use of the same amount of alcohol) • The characteristic alcohol withdrawal syndrome or drinking (or using a closely related substance) to relieve or avoid withdrawal symptoms. The severity of AUD is defined by the number of occurring criteria: 2−3, mild; 4−5, moderate; 6 or more, severe.4 According to a World Health Organization report in 2014, the harmful use of alcohol ranks among the top five risk factors

Figure 1. Current medications. 1746



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first-line therapy.13,14 Interestingly, the average treatment effect size for compound 4 was shown to be 0.53 compared to the relatively modest effect sizes of 0.28 and 0.26 for compounds 1 and 3, respectively.16 Compound 5 is FDA-approved as a muscle relaxant and as an antispastic agent. It is an agonist of GABAB receptors. It has been proven to reduce withdrawal symptoms, and some studies have demonstrated that it is effective in patients who desire abstinence, even at a low dose (30 mg). Compound 5 appears to be effective, especially in reducing craving. A recent study has shown no efficacy of compound 5 against abstinence.17 The clinical study results are still contradictory, and debate continues regarding an effective dose because some studies demonstrated compound 5 efficacy at a low dose. Other studies where titration was performed showed that some patients responded to a low dose and other patients had no response to higher doses. Nonetheless, the most common limitations of the treatment are its side effects and coexisting psychiatric diseases.18,19 While side effects with this compound are common but generally benign and minor, they can occasionally be severe: fatigue, sleepiness, insomnia, dizziness, various forms of pain, paresthesia, and nausea are the most frequently observed side effects. A recent French national report has indicated that self-poisoning with compound 5 in alcoholdependent patients can be a critical concern.20 High compliance and regular supervision by a physician are required. In March 2014, the French National Safety Agency for Medicines and Health Products (Agence Nationale de Sécurité des Médicaments et des produits de santé, ANSM) issued a temporary recommendation for use (TRU) (ANSM, 2014)21 pending the results of two efficacy-related French trials regarding high doses of compound 5 (up to 180 mg). Due to controversial studies suggesting low efficacy or even ineffectiveness of topiramate (6), this compound is not FDAapproved for AUD treatment. Known as a therapeutic for epilepsy and migraines, compound 6 is well-tolerated and sometimes prescribed off-label to treat various behaviors related to AUD. Compound 6 is both an agonist of GABAA and an antagonist of AMPA and kainate glutamate receptors. Compound 6 reportedly improves health issues caused by AUD, such as hypertension, high cholesterol, obesity, and liver abnormality. Nevertheless, it is unclear whether these benefits result from the treatment itself or from the cessation of alcohol intake.13,14 Other good candidates for AUD therapy include additional molecules targeting the GABA system, such as gabapentin, or the serotoninergic system, such as ondansetron. For more effective and efficient treatments a personalized approach has been proposed to better match the treatment to the patients’ characteristics, such as their disease phenotype or genetic factors.15 Given the high heterogeneity of AUD increasing the therapeutic arsenal is a necessity to adapt treatment to each patient. In this context, a better understanding of the mechanisms underlying AUD is urgently needed. 2.3. Mechanisms. Vulnerability to developing AUD depends on the complex interaction between genetic and epigenetic factors. Both acute and chronic alcohol exposure have been shown to be associated with changes in brain gene expression and, more recently, to changes in epigenetic markers, such as DNA methylation and histone acetylation.22,23 Results obtained in genetically selected rats for their alcohol preference (alcohol preferring P rats) demonstrated that their genetic predisposition to anxiety and to high alcohol intake was

Contemporary medications mainly target the corticomesolimbic dopamine system whose activity is responsible for both reward and relapse after abstinence. Dopamine neurons from the ventral tegmental area release dopamine in the nucleus accumbens, and this release is associated with reinforcement and learning phenomena such as reward error prediction.13 Alcohol can activate dopaminergic neurons directly or indirectly by releasing endorphins and inhibiting GABAergic inhibitory neurons. Dysfunction of this system has been shown to be involved in AUD. The reinforcing effects of alcohol are mediated by four neurotransmitter systems: gamma-aminobutyric acid (GABA), opioids, glutamate, and serotonin (5HT). The first two have an inhibitory effect, whereas the last two are characterized by an excitatory effect on dopaminergic neurons. AUD medications should directly or indirectly regulate the dopaminergic system. Compound 1 is an antagonist of μ-opioid receptors that blocks alcohol-induced dopamine release by increasing endorphin levels (Figure 1). Compound 1 was approved for the treatment of alcohol dependence by the FDA in 1994 and by the European Medicines Agency in 1996. The drug is used to minimize craving in alcohol-dependent patients and is effective in reducing alcohol intake during relapse. This drug is thus considered to be an “anti-reward craving” therapy. The most common side effects of this drug are nausea, drowsiness, lack of energy, headache, decreased alertness, anxiety, and depression, although they do not appear frequently; compound 1 has an excellent safety profile overall.13−15 As with compound 1, compound 2 is an antagonist of μopioid receptors, but it is also a partial agonist of κ-opioid receptors. It is now prescribed in several European countries to reduce alcohol intake in alcohol-dependent patients, and patients take the drug “as-needed” (defined as self-identified high risk situations). It may reduce both positive and negative reinforcements. Positive reinforcement is the rewarding effect of alcohol, while negative reinforcement is the motivation to drink alcohol to alleviate withdrawal/negative symptoms (dysphoria, stress, anxiety), which is another side of alcohol addiction, called the “dark side”. Compound 3 (calcium salt of acetyl homotaurine) was approved by the FDA in 1989 to reduce relapse and maintain abstinence in patients with AUD. Compound 3 has excitatory effects on the GABA system and inhibits the glutamatergic system by binding to the mGluR5 and NMDA receptors, respectively. Its major side effect observed during overdose, is diarrhea, and the medication is characterized by a favorable tolerability and safety profile.13−15 Compound 4 (Antabuse) is the oldest and best known drug to prevent relapse after detoxification from alcohol. The mechanism of 4 differs significantly from those described above. The aim of this therapy is to induce aversion against alcohol, but it does not reduce craving. Alcohol is metabolized to toxic acetaldehyde, rapidly transformed into acetate and then excreted. Compound 4 is an inhibitor of aldehyde dehydrogenase; it suppresses the oxidation of acetaldehyde into acetic acid, thus significantly repressing its metabolism to cause an accumulation of the toxin. Alcohol consumption, even in small amounts, after taking compound 4 leads to the disulfiram effect, characterized by hypotension, tachycardia, flushing, diaphoresis, dyspnea, nausea, and vomiting. Compound 4 has good efficacy based on high compliance but has life-threatening effects if alcohol is consumed. Although the medication has been FDA-approved since 1951, it is not recommended as a 1747



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partially due to higher HDAC-2 expression in the amygdala, a brain region involved in anxiety, emotions, and conditioning.1 In addition, acute alcohol exposure decreased both HDAC-2 activity and the levels of HDAC-2 in the amygdala of alcohol preferring P rats but not in alcohol avoiding NP rats (see 3.1 for details).24 Acute and chronic exposure to alcohol and alcohol withdrawal have been shown to cause the histone acetylationpromoted expression of numerous genes.25,26 Alcohol-induced changes in histone acetylation may play a crucial role in the neuroadaptations that may ultimately contribute to the development of AUD.27 In both animals and humans, chronic alcohol consumption increases HDAC gene expression in peripheral blood, whereas binge drinking reduces HDAC gene expression.28 We have recently demonstrated altered histone H3 acetylation levels in several brain regions from the reward circuit of rats made dependent to alcohol after chronic and intermittent exposure to ethanol vapor.29 We, along with others, have recently established that acute alcohol exposure can inhibit HDAC activity and increase histones H3 and H4 acetylation in different rat brain structures associated with AUD.22,30−32 The role of epigenetics has been shown after repeated injections of ethanol in mice displaying behavioral sensitization to the stimulant motor effects of ethanol.22 Behavioral sensitization is commonly used in the addiction field to investigate neuroadaptations occurring after escalation of drug intake and relapse after a period of abstinence, and it is considered as a model of drug-induced neuroplasticity. This model of neuroplasticity has been presented to be associated with changes in the expression of specific genes involved in epigenetics and is blocked by sodium butyrate, a nonspecific HDACI.23 For example, we have also shown that HDAC-1 mRNA levels are increased after acute alcohol injection and repeated ethanol injections in the striatum.23 Considering all the mechanisms described above involving HDAC-1 and HDAC-2, two isoforms of class I HDACs could credibly be an effective treatment for AUD.1 However, it is important to note that several studies using nonselective HDACIs, such as vorinostat (7) and trichostatin A (8) (Figure 2), have suggested that targeting HDACs should be useful in treating AUD.31,33,34

Systemic administration of compound 7 (50 and 100 mg/kg) decreased alcohol intake in mice by 40%. The reduction of alcohol intake lasted if the mice were treated with compound 7, but the effect was only present for 1 day post-treatment. The same authors demonstrated that the systemic administration of compound 7 (50 mg/kg) decreased alcohol operant selfadministration by 20% in rats. The effect of compound 7 is selective to alcohol and has no effect on sucrose intake.34 Compound 8 (0.1, 0.2, and 0.4 mg/kg) has also been shown to be effective in reducing ethanol intake in mice.34 In P rats, compound 8 (2 mg/kg, daily administration during the final 3 days of a 10-day period of a two-bottle choice paradigm using water and 9% ethanol solution) decreased ethanol intake from 7.0 g/kg to less than 1.0 g/kg.35 Treating P rats during alcohol withdrawal with compound 8 also attenuated anxiety-like behavior and normalized HDAC activity and deficits in histone acetylation.33 Sodium butyrate (9), an inhibitor of class I and IIa HDACs, has exhibited promising results in different animal models of AUD. Compound 9 prevented the induction (escalation of response to the hyperlocomotor effect of ethanol) and reversed the expression (higher response to the locomotor effect of ethanol after a short or extended drug abstinence period) of ethanol-induced behavioral sensitization in mice. The authors proposed expression inhibition of either HDAC-1 or HDAC-2 in the striatum as a putative mechanism.23 Compound 9 has been shown to be very effective in reducing ethanol intake in a model of consumption escalation in rats. In the ethanol intake escalation model, rats have access to a 20% ethanol solution every other day (access to ethanol during three 24 h sessions a week). Indeed, Simon O’Brien et al.29 have demonstrated that compound 9 either prevented ethanol intake escalation or reduced intake once rats escalated their consumption. Compound 9 was also effective in totally blocking the rebound of ethanol intake in the model of ethanol deprivation effects, which is a long-standing behavioral model of alcohol craving and relapse. The same authors have also demonstrated that compound 9 (administered either intraperitoneally at 600 mg/ kg or intracerebro-ventricularly) was very effective in reducing ethanol intake in dependent rats that were exposed to chronic and intermittent ethanol vapor to induce both physical and psychological dependence because it totally blocked the excessive alcohol intake compared to that of the control group animals. Compound 9 had no effect on sucrose selfadministration. The effects of compound 9 on alcoholdependent animals were observed on the second day (second injection) and were mimicked by compound 10, a more selective inhibitor of class I HDACs.29 Thus, this study offers a new perspective for the use of more selective HDACIs. In this regard, compound 10 (10 mg/kg once a day via the intraperitoneal route) decreased the operant alcohol selfadministration (after the second injection, as seen for compound 9) in alcohol-dependent rats. The fact that both drugs significantly decreased alcohol consumption after only the second day suggests that the observed behavioral effects were mediated through changes in gene expression. In addition, the fact that the administration of HDACI directly via the intracerebro-ventricular route was effective in reducing alcohol intake confirmed that the behavioral effect was not mediated through peripheral side effects. The effects of compound 10 were also tested in another animal model for their response to alcohol.34,36 The drug was tested in a model of voluntary heavy drinking. After two

Figure 2. Nonspecific HDACIs.

Compound 7 is an FDA-approved pan-HDAC inhibitor that has been shown to reduce alcohol intake in mice and rats at 50−100 mg/kg.34 In this study, mice had intermittent access to 20% alcohol for 4 h beginning 2 h into the dark cycle, promoting high levels of alcohol intake (∼7 g of pure ethanol/ kg of body weight per 4 h that generated pharmacologically relevant blood alcohol concentrations of ∼100 mg/dL).34 1748



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Scheme 1. Proposed Mechanism of Alcohol Addiction

scanning period of 90 min. Compound 10 reportedly has good metabolic stability and a relatively long half-life (t1/2 = 33.9 h) when administered orally. However, increased dose and frequency of administration disrupt the half-life (t1/2 = 52− 150 h).40 Altogether, numerous studies have shown the efficacy of several compounds targeting HDACs on different behavioral components of alcohol intake using animal models. Recent reviews have proposed explanations of how epigenetics and especially HDAC enzymes may play a critical role in the development of alcohol addiction. Krishnan et al.41 proposed that a mechanism of the alcohol addiction process may involve chromatin remodeling in the amygdala (Scheme 1).1,7 Acute ethanol intake leads to relaxed chromatin and euphoric effect. After repeated alcohol exposure, several neuroadaptations occur and induce a chronic tolerance to alcohol. Then, condensed chromatin upon withdrawal leads to negative effects (anxiety, depression). Subjects tend to self-medicate to achieve a feeling similar to that resulting from their first alcohol exposure resulting in alcohol abuse and, finally, in addiction. To prevent alcohol dependence, HDACIs are proposed to restore normal chromatin and thus to counteract dysregulation of gene transcription. There are two likely explanations for HDACI efficacy: (1) They enable specific changes in gene expression that are inhibited by alcohol intake. (2) The reduced gene expression caused by alcohol intake requires an increase in specific gene products. The preference for HDAC-1 and HDAC-2 specific inhibitors is supported by the fact that the first should reduce excessive ethanol intake, motivation for ethanol consumption, and relapse after abstinence,36 and the second should prevent anxiety and reduce alcohol consumption.33 2.4. Class I HDACIs in Other Brain Disorders. HDACIs may also be of great interest in the pharmacotherapy of other psychiatric disorders.42,43 Evidence derived mostly from a large body of research in animal models suggests that histone modifications also play an important role in psychiatric diseases, including depression, anxiety, fear, and schizophrenia.38

months of excessive alcohol intake in rats, different doses of compound 10 were injected intracerebro-ventricularly. After the second injection of 500 μM compound 10, operant alcohol self-administration was decreased by 75%, the motivation to consume was decreased by 25%, and the relapse phenomenon after a period of abstinence was decreased by 50%.36 Warnault et al.34 have also demonstrated that compound 10 (5.0, 10, and 20 mg/kg) decreased alcohol intake in mice. It is noteworthy that targeting only one isoform of class I HDACs may be effective in treating AUD because using a small interfering RNA targeting HDAC-2 has been shown to reduce both alcohol intake and anxiety-like behavior in alcoholpreferring rats.1 Altogether, the results demonstrated that class I HDACIs are effective in reducing alcohol intake and relapse in rats displaying excessive alcohol intake, innate alcohol preference, or alcohol dependence. A challenge when treating brain disorders is overcoming the permeability of the compound across the blood−brain barrier (BBB). So far, several drugs, including compounds 7, 8, 9 and 10, have been shown to cross the BBB, but some drugs display poor BBB penetration. In addition, compound 10 has been demonstrated to be brain region selective and is 30−100-fold more potent than valproic acid (VPA) in increasing histone acetylation in vivo.37 In 2010, compound 10 was considered a second-generation HDACI with improved specificity (because of its high specificity toward HDAC-1). This held promise not only for cancer treatment but also for treatment of various psychiatric disorders.38 Most of the physical and chemical characteristics of compound 10 appear favorable for BBB penetration, including its low molecular weight, its nonionic structure at physiological pH (7.4), and its lipophilic properties (log D = 1.8, log P = 2.5).39 However, the total tissue distribution volume (VT = 0 mL/ cm3) and polar surface area (PSA = 119.2 Å2) cause compound 10 to have poor brain entry. PSA is a critical property for brain uptake and must not be greater than 65. Pharmacokinetic studies for [11C] of the carbamate function of compound 10 using positron emission tomography (PET) described very low BBB penetration and poor brain uptake (250-fold in comparison to other isoforms) (Figure 15).97 Benzamides

Figure 15. Compound 27 structure and HDAC activity. 1757



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CL1−5), although it shows no cytotoxicity in normal cells (IMR-90) (Figure 18). HDAC-8 might be a therapeutic target for acute myeloid leukemia.109 Efforts to exploit the malleability of the HDAC-8 active site and its unique, active subpocket has resulted in selective inhibition of compound 33 toward HDAC-8 (Figure 18). The most potent compound is 150-fold more selective toward HDAC-8 than HDAC-1 and HDAC-6. The aryl linker inhibitor binds HDAC-8 with movement of Phe152 away from its initial state packed against Met274, exposing a large subpocket.110 Compound 34 (PCI-34051) inhibits HDAC-8 with greater than 250-fold more selectivity over the other HDACs and induces apoptosis of cells derived from T cell lymphomas (Jurkat and HuT78) (Figure 18). Researchers discovered a mechanism of action unique to the HDAC field that involves Ca2+ flux signaling via PLCγ1. This mechanism of action suggests less toxicity than the broad-spectrum HDACIs and might prove to be useful in the treatment of T cell-derived malignancies.111 The physical and chemical characteristics of compound 34 (log P = 2.61; PSA = 61.8 Å2; standardized uptake volume (% tracer conc in hippocampus @20 min): %SUV@20 min = 30; brain to plasma ratio (hippocampus/plasma): B/P@20 min = 0) suggest poor brain penetration of this compound.112 Recently, a novel hydroxamic acid derivative, compound 35, was identified as an HDAC-8 selective inhibitor by repurposing an existing small molecule library at the Boston University Center (Figure 19).113 The trisubstituted-triazole scaffold of compound 35 is more potent (10-fold) and more selective (1500-fold higher against HDAC-8 than HDAC-6) than what is reported for compound 34. Tropolone 36 is a derivative from the natural compound βthujaplicin90 without a capping group (1400-fold more selective toward HDAC-8 than HDAC-4) (Figure 19). It is known as a treatment for T cell lymphoma. HDAC-8 inhibition by tropolones can be explained by branching at the β position so that the isopropyl group extends into a hydrophobic pocket. HDAC-8 has a Trp141 instead of Leu139 (HDAC-1) at the bottom of the cavity, which accommodates small hydrophobic groups. Compound 37 presents a different metal binder appendage, as it has a pyrrolidine group that compound 22 lacks, which causes different affinity and selectivity (Figure 20). Compound 37 presents no activity against other isoforms. The ZBG is less

in the recently described Cornelia de Lange syndrome (CdLS), which is a congenital malformation disorder.100,101 Some compounds are described as being selective HDAC-8 inhibitors. However, not all HDACs have been tested; there is no comparison between the inhibition of classes I and II.102−105 We have focused on compounds 30−37, which are HDAC-8 selective inhibitors with high selectivity among the HDACs tested and representative of both classes of HDACs. Compound 30, a small molecule with a dichlorophenyl moiety, exploits the acetate release channel and achieves HDAC-8 selectivity (Figure 17). It has an alternative chiral α-

Figure 17. Compound 30 structure and HDAC activity.

amino-ketone metal binding warhead moiety to access the internal cavity. This chirality is essential to inhibition. The dichlorophenyl part provides π-stacking interactions with Trp141 at the bottom of the HDAC-8 cavity, which does not exist in HDAC-1. The isoindole provides favorable T-shaped πstacking interactions with Phe152 in the channel. The compound can be used for the treatment of cancerous and parasitic diseases.106 Compound 31 (NCC149) has a U-shaped conformation in the active site of HDAC-8 and contains a triazole ring. Compound 31 was obtained using click chemistry, interacts through a CH−π interaction with the methylene group of Phe152 (subpocket) and is a potent HDAC-8 inhibitor (Figure 18). This HDACI binds to a unique hydrophobic pocket (formed by Trp141, Ile34, and Pro35) by its phenylthiomethyl group.107,108 The orientation of the phenylthiomethyl and hydroxamate group appears significant, as the selectivity was improved 34-fold versus HDAC-6 and more than 543-fold for the others. This compound has inhibitory effects on T cell lymphoma and neuroblastoma cells, thus showing the potential of HDAC-8 selective inhibitors as anticancer agents. Compound 32 displays high selectivity for HDAC-8 (111fold greater than toward HDAC-1 and HDAC-3) and has cellular effects in lung cancer cell lines (A549, H1299, and

Figure 18. Structure of HDAC-8 inhibitors. 1758



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Figure 19. Structure and HDAC activity of compounds 35 and 36.

much more stable than compound 38 in media and sera. The macrolide can be accommodated in the 11 Å pocket of the protein surface entrance of the hydrophobic channel, which establishes van der Waal interactions and hydrogen bonds.56 Other family members of HDAC-1 and HDAC-2 inhibitors have the same metal binding moiety (benzamide). They have a lower selectivity to HDAC-1 compared to HDAC-2. Incorporation of a biaryl zinc-binding motif results in an enhanced selectivity and potency compared to HDAC-3 (selectivity >1000-fold for HDAC-1 versus HDAC-3). They could be used as anticancer agents due to their antiproliferative properties. The aminophosphonate 39 is an analogue of the malonate 16 that displayed tumor growth inhibition in xenograft studies (HCT116 cells) and superior pharmacokinetic properties. It was very well tolerated at all doses tested (Figure 22).115 Compound 40 (Cpd-60) is a potent, slow-binding inhibitor that is more selective toward HDAC-1 and HDAC-2 than the other HDAC isoforms. It was potent in the HCT116 proliferative assay and had good rat pharmacokinetic properties (intravenous dosing, 2.0 mg/kg; t1/2 = 9.7 h; oral dosing, 4.0 mg/kg; oral bioavailability, F = 64%).82 It was investigated as a treatment for depression and as a mood stabilizer.86 Compound 40 exhibits more sustained brain exposure (intraperitoneal dosing: 45 mg/kg; t1/2 = 6.44 h) compared to compound 7 (intraperitoneal dosing: 25 mg/kg; t1/2 = 0.44 h). Compound 40 is a brain penetrant compound with more selectivity and slow-on/slow-off binding for HDAC-1 and HDAC-2 (t1/2 = 40 h and t1/2 = 80 h, respectively) compared to compound 7, which has fast-on/fast-off binding kinetics (t1/2 < 4 min for HDAC-1, HDAC-2, and HDAC-3). Selective inhibition of HDAC-1 and HDAC-2 in the brain may be an epigenetic mechanistic target for the development of therapeutics for mood disorders. Incorporation of a spirocycle enhanced the HDAC-1 inhibitory activity of the nicotinamide derivatives (Figure 22). Compound 41, a biaryl-spirocyclic-nicotinamide, is a selective inhibitor against HDAC-1 and HDAC-2 that has antitumor activity (HCT116 cells).116 Its pharmacokinetic profile is promising, as it has higher quantitative bioavailability in dogs than rats [(intravenous dosing: 2.0 and 0.5 mg/kg; t1/2 = 6.2 h and t1/2 = 6.7 h for rats and dogs, respectively); (oral dosing, 4.0 and 1.0 mg/kg; oral bioavailability, F = 23% and F = 100% for rats and dogs, respectively)]. Unfortunately, its safety profile was unacceptable due to hERG binding affinity, whereas compound 42 was well-tolerated because it is modified such that the hERG activity is attenuated (spirocyclic carbamate group) and has acceptable pharmacokinetic properties [(intravenous dosing, 2.0 and 0.5 mg/kg; t1/2 = 4.2 h and t1/2 = 1.4 h for rats and dogs, respectively); (oral dosing, 4.0 and 1.0 mg/ kg; oral bioavailability, F = 28% and F = 17%; PPB = 99.8%; PPB = 97.6% (at 2 μM) for rats and dogs, respectively)].117 Compound 42 is a time-dependent, substrate-competitive, reversible inhibitor that has relatively slow binding kinetics.


bulky, thus allowing fewer interactions with the hydrophobic internal cavity of HDAC-2. The hydrophobic internal cavity is smaller in HDAC-8 than in HDAC-1 and HDAC-2 and can thus accept smaller groups such as the pyrrolidine cycle.56 A small capping group is also present on different molecules, but it is not necessary for inhibitory activity, as shown with compound 36. Among inhibitors 30−37, five hydroxamic acid compounds are selective for HDAC-8, and the others possess α-hydroxyketone or amide functions. Hydroxamic acid is known to be the best potent ZBG, but it is also toxic and has undesirable side effects. 4.3.5. Dual HDAC-1 and HDAC-2 Inhibitors. The development of selective inhibitors of HDAC-1 or HDAC-2 is difficult due to their very high sequence similarity. The difference in these two proteins is the metal ion situated approximately 7 Å from the Zn2+ ion, which is a K+ ion in HDAC-1 and a Ca2+ ion in HDAC-2.89 The compounds described below have a higher selectivity for HDAC-1 and HDAC-2 compared to the other isoforms. Selective HDAC-1 and HDAC-2 inhibitors may be a valuable tool for the development of treatments for CNS disorders (psychiatric and neurodegenerative) and alcohol addiction (see section 2.3). Compound 11, a cyclodepsipepside, is an effective drug for treating T cell lymphoma. It acts as a natural prodrug in that it is activated in cells and strongly inhibits HDACs. HDAC-1 and HDAC-2 are more strongly inhibited by its reduced form, compound 38 (red-FK228), than HDAC-4 and HDAC-6 (Figure 21).114 Compound 38 has two thiol groups, one of which interacts with the active site zinc ion. Compound 11 is

Figure 21. Compound 38 structure and HDAC activity. 1759



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Figure 22. Structure of HDAC-1 and HDAC-2 inhibitors.

hydrophobic internal cavity. The phenyl ring interacts with the surrounding hydrophobic residues, while the bidentate coordination increases the affinity for HDAC-1 and HDAC-2. Some of these compounds have good pharmacokinetic properties and excellent brain penetration, and they may be potent candidates for treatment of AUD.

Compound 43 (BRD4884) is described as a kinetic selective HDAC-1 and HDAC-2 inhibitor (Figure 23).118,119 The free

5. CONCLUSIONS AND PERSPECTIVES While some molecules are effective in reducing alcohol intake as well as maintaining abstinence, new drugs that have new mechanisms of action are needed to treat AUD. Indeed, the available medications are effective, but the effects are modest. Because personalized medicine, where one medication may be effective for one patient and not for the other, is the way of the future, progression from one-size-fits-all treatment to medication and treatment matching must be made. However, this Perspective requires a sufficient number of effective treatment options. New treatments with original mechanisms of action may also be very useful for combination treatment. It is reasonable that combining treatments that have different mechanisms of action may improve the outcome. This is consistent with the fact that numerous ongoing trials (ClinicalTrials.gov Web site) are currently testing the efficacy of combined therapies to treat AUD. Here, we have described a potential new epigenetic therapy based on HDAC enzymes and, more specifically, class I HDACs. Indeed, while the first studies exhibited nonselective HDACI efficacy, the more recent studies have shown that targeting a specific class is also effective in preventing and/or curing several aspects of the disease in AUD different animal models. Class I HDACs have been implicated in many pathological processes (cancer, psychiatric and inflammatory disorders, and infectious diseases). This review and other reviews of psychiatric disorders suggest that HDACIs, specifically class I HDAC selective inhibitors, should have therapeutic applications in AUD, although mechanisms involved in these pathological processes are not clearly defined.46 However, the design and synthesis of isoform-selective derivatives clearly depend on HDAC isoform structure.


aniline function of the benzamide coordinates the zinc ion, and the anilide −NH forms a H-bond with the backbone carbonyl oxygen of Gly154. The tetrahydropyran moiety provides van der Waal interactions within the 11 Å lipophilic channel in a preferential chair conformation. Finally, the phenyl ring of compound 43 is sandwiched between Met35 and Leu144, and the para-fluorine atom points toward Phe114 into the 14 Å internal cavity. Compound 43 provides better thermodynamic (IC50) selectivity for HDAC-1 and HDAC-2 than HDAC-3 and better kinetic selectivity (half-life) for HDAC-2. Compound 43 is a slow-on/slow-off kinetic inhibitor of HDAC-2 and shifts to faston/faster-off kinetic inhibition against HDAC-1, leading to a 7fold longer half-life against HDAC-2 (t1/2 = 143 min) than HDAC-1 (t1/2 = 20 min). Compound 43 displays good pharmacokinetic properties in mice (intraperitoneal dosing: 10 mg/kg, t1/2plasma = 0.87 h and t1/2brain = 0.65 h), and has excellent brain permeability (brain plasma ratio of 1.29), making it a suitable candidate for CNS applications. To summarize, the size of the capping group is certainly important to govern class selectivity as shown with the most potent cyclic peptide derivative, compound 38. However, HDACIs with smaller capping groups display class I HDAC selectivity by cluttering the internal cavity such as compound 43. The thiophenyl part of the metal binding occupies the 1760



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treatment, there is considerable opportunity for further study and application of HDACIs based on promising results with compounds 7, 8, and the more interesting compound 10, which selectively inhibits HDAC-1. HDACIs, specifically those targeting class I HDACs, are promising because numerous studies have shown their ability to reduce several aspects of AUD, including excessive alcohol intake, loss of control, relapse, and alcohol withdrawal-induced anxiety. Compounds 40 and 43 are dual HDAC-1 and HDAC-2 inhibitors. Their physical and chemical characteristics are favorable for BBB penetration, and they are good candidates to be used in the treatment of CNS pathologies. Because they have an ideal product profile, their efficacy in treating AUD should be explored. Efforts in medical research must be made to discover an HDACI with improved class I selectivity, greater tolerability, bioavailability, and BBB permeability. Such medications may be effective in reducing alcohol intake, maintaining abstinence, and reducing craving.

To summarize, some structural data regarding HDACs are highlighted. HDAC-3 is different from all other isoforms in that it has a solvent-exposed tyrosine (Tyr198) on its surface. Structure analysis of HDAC-8 revealed a deep hydrophobic pocket adjacent to the active site channel, allowing the design of HDAC-8 selective compounds that interact with both the active site Zn2+ ion and this subpocket. Class I enzymes have an internal pocket at the bottom of the tube-like channel leading to the zinc ion. This 14 Å hydrophobic internal cavity is formed by the same residues for all class I isoforms, with minor differences. HDAC-1, HDAC-2, and HDAC-3 in that order contain the longest cavities, and HDAC-8 has the smallest cavity. These attributes can be exploited to design selective compounds for class I HDACs. While HDAC-1 and HDAC-2 have a high amino acid sequence identity, the catalytic pockets of these isoforms have different dimensions due to differences in the residues neighboring the catalytic cavity. This internal cavity can be useful to dictate class I isoform selectivity, as a metal binder (even a weak binder) was able to maximize the interactions within this pocket. Finally, we reviewed the literature regarding published compounds reported to be selective inhibitors of class I HDACs and provided the activity and selectivity for all the isoforms tested. HDACIs with a macrolide element or a bulky branched substituent in the capping group region are selective for class I HDACs, suggesting that these groups play an important role in differentiating HDAC isoforms. However, inhibitors without a capping group, such as compounds 17, 20−21, and 36, display a potent selectivity toward HDAC-1, HDAC-2, and HDAC-8, respectively. All of the compounds described contain either a phenyl group, an alkyl chain, or a polar amide bond as the linker, and these spacers can create π−π stacking or CH···π interactions with Phe in the hydrophobic channel. Many class I-selective HDACIs contain a benzamide as the metal binding group, except for HDAC-2 and HDAC-8 selective inhibitors, which possess either hydroxamic acid or α-hydroxyketone or amide functions. Some compounds reportedly display relative HDAC-1 and HDAC-2 selectivity or preferential inhibition. Despite much effort, truly selective compounds are rare, and there are no precise structural characteristics that ultimately achieve selective inhibition of one HDAC isozyme over the others. The most potent HDACI toward HDAC-1 is compound 18, which is as active as compounds 39−42 and has higher selectivity toward HDAC-1 than HDAC-3 and HDAC-8. Compound 22 is less potent than compounds 39−42 but has high selectivity toward HDAC-2. Thus, far, most of the HDACIs identified in the literature are used for cancer therapy120 and, to the best of our knowledge, no HDACI has been tested to treat psychiatric diseases. Interestingly, only a few clinical studies can be found on ClinicalTrials.gov that may encourage future studies in the fields of alcoholism and psychiatry such as the NCT02654405 (“Sodium Butyrate For Improving Cognitive Function In Schizophrenia”) and the NCT03056495 (“Clinical Trial to Determine Tolerable Dosis of Vorinostat in Patients With Mild Alzheimer’s Disease”) trials. Only a few HDACIs have been tested in preclinical studies for AUD and other psychiatric diseases, but the results are promising. Regarding AUD

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AUTHOR INFORMATION

Corresponding Authors

*For E.B: phone, +33-326913733; fax, +33-326918029; E-mail, [email protected]. *For M.N: phone, +33-322827672; E-mail, [email protected]. ORCID

Erika Bourguet: 0000-0003-3346-0372 Katarzyna Ozdarska: 0000-0002-4993-9057 Gautier Moroy: 0000-0002-8973-0477 Notes

The authors declare no competing financial interest. Biographies Erika Bourguet received her Ph.D. in Organic Chemistry from the University of Montpellier II in France in 2000, after which she completed a two-year postdoctoral appointment with Prof. D. Schinzer at the Chemisches Institut of the University of Magdeburg (Germany). She then worked for two years with Prof. J. D. Brion in the BioCIS laboratory (UMR-CNRS-8076) at the University of Châtenay− Malabry (France). In 2004, she was appointed Associate Professor of Organic Chemistry at the Reims Institute of Molecular Chemistry (UMR-CNRS-7312) at the University of Reims Champagne−Ardenne (France), and she obtained habilitation in 2011. Her first research topics were the synthesis of peptide mimetics (RGD, β-strand/sheet) and total synthesis of natural compounds (Epothilone, Trungapeptin). She then shifted her research interests to the development of metalloenzyme inhibitors (MMPI, HDACI). Katarzyna Ozdarska graduated from the Faculty of Pharmacy of the Medical University of Warsaw in 2016. Her master’s thesis was entitled, “Synthesis of Bisarylsulfonylhdrazide HDAC Inhibitors”. The experimental study and thesis preparation were carried out at the Faculty of Pharmacy at the University of Reims Champagne−Ardenne (France) in cooperation with the Department of Bioanalysis and Drug Analysis at the Medical University of Warsaw (Poland). In 2016, she began her doctoral studies at the Medical University of Warsaw in collaboration with the University of Reims Champagne−Ardenne. She is studying the synthesis and biological assays of HDAC inhibitors. Furthermore, she is working in a genetic laboratory department at the hospital in Warsaw (Poland). Gautier Moroy received his Ph.D. in 2005 from the University of Reims Champagne−Ardenne in France. After postdoctoral appoint1761



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ments at the University of Strasbourg in France (2006-2008) and the Swiss Institute of Bioinformatics in the University in Lausanne, Switzerland (2008-2009), he joined the Paris Diderot University in France as lecturer of bioinformatics. His research interests focus on structural bioinformatics, molecular modeling, and in silico drug design.

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REFERENCES

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Jérôme Jeanblanc, Ph.D., is a neuroscientist whose research focuses on animal models of alcohol-associated behaviors and on identifying the intracellular mechanisms underlying these behaviors within the Research Group on Alcohol and Pharmacodependences in Amiens (France). In addition, Jérôme Jeanblanc has expertise in neuropharmacology and neurochemistry and worked on the epigenetic mechanisms involved in alcohol consumption in rodents. In parallel, Dr. Jeanblanc is a member of the local ethical committee, and he is the referee for Animal Welfare at the University Center for Health Research. He is the author of 17 peer-reviewed articles (10 as the first author) and one book chapter. Dr. Jeanblanc has participated in numerous international and national meetings (13 oral communications and more than 30 posters). Mickaël Naassila, Ph.D., is an internationally recognized expert on alcohol and the neurobiology of alcohol addiction. He is a professor of physiology at the pharmacy school at the University of Picardie Jules Verne in Amiens. He received his Ph. D. in 1998 at the University of Rouen and was a postdoctoral fellow in the Pharmacology and Toxicology Department of the University of Kansas. His scientific career has been devoted to the neurobiology of alcoholism, and he is the author of more than 50 peer-reviewed scientific papers. He is the director of the Research Group on Alcohol & Pharmacodependences (GRAP INSERM ERi 24). He is a member of the National Academy of Pharmacy and the recipient of the “fight against alcoholism” award from the National Academy of Medicine.

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ACKNOWLEDGMENTS Support from SFR CAP-Santé, Université de Reims Champagne−Ardenne, Université de Picardie, Conseil Régional de Picardie, CNRS, Ministère de l’Education Supérieure et de la Recherche (MESR), is gratefully acknowledged. Monika Moczarska and Magdalena Szmigielska are gratefully acknowledged for their help. Jocelyne Wuibout is warmly acknowledged.

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ABBREVIATIONS USED ADME, absorption, distribution, metabolism and excretion; AUD, alcohol use disorder; BBB, blood−brain barrier; CNS, central nervous system; CTCL, cutaneous T cell lymphoma; DNA, deoxyribonucleic acid; DSM, diagnostic and statistical manual of mental disorders; ERK, extracellular regulated kinase; FDA, Food and Drug Administration; GABA, gammaaminobutyric acid; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACI, histone deacetylase inhibitor; HDLP, histone deacetylase like protein; hERG, human ether-ago-go-related gene; 5-HT, 5-hydroxytryptamine; mGluR5, metabotropic glutamate receptor 5; MM, multiple myeloma; mRNA, messenger ribonucleic acid; NAD+, nicotinamide adenine dinucleotide; NMDA receptors, N-methyl-D-aspartic acid receptors; PDB, Protein Data Bank; PET, positron emission tomography; PPB, plasma protein binding; PSA, polar surface area; PTSD, post-traumatic stress disorder; Rpd3, reduced potassium dependency; SIR, sirtuin; Sir2, silent information regulator; SSAR, stereo/structure−activity relationship; ZBG, zinc binding group 1762



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