Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy

Immune checkpoint factors, such as programmed cell death protein-1/2 (PD-1, PD-2) or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptors, are targets for monoclonal antibodies (MAbs) developed for cancer immunotherapy. Indeed, modulating immune inhibitory pathways has been considered an important breakthrough in cancer treatment. Although immune checkpoint blockade therapy used to treat malignant diseases has provided promising results, both solid and haematological malignancies develop mechanisms that enable themselves to evade the host immune system. To overcome some major limitations and ensure safety in patients, recent strategies have shown that combining epigenetic modulators, such as inhibitors of histone deacetylases (HDACi) or DNA methyltransferases (DNMTi), with immunotherapeutics can be useful. Preclinical data generated using mouse models strongly support the feasibility and effectiveness of the proposed approaches. Indeed, co-treatment with pan- or class I-selective HDACi or DNMTi improved beneficial outcomes in both in vitro and in vivo studies. Based on the evidence of a pivotal role for HDACi and DNMTi in modulating various components belonging to the immune system, recent clinical trials have shown that both HDACi and DNMTi strongly augmented response to anti-PD-1 immunotherapy in different tumour types. This review describes the current strategies to increase immunotherapy responses, the effects of HDACi and DNMTi on immune modulation, and the advantages of combinatorial therapy over single-drug treatment

SIRT3 Activation a Promise in Drug Development? New Insights into SIRT3 Biology and Its Implications on the Drug Discovery Process

: Sirtuins catalyze deacetylation of lysine residues with a NAD+-dependent mechanism. In mammals, the sirtuin family is composed of seven members, divided into four subclasses that differ in substrate specificity, subcellular localization, regulation, as well as interactions with other proteins, both within and outside the epigenetic field. Recently, much interest has been growing in SIRT3, which is mainly involved in regulating mitochondrial metabolism. Moreover, SIRT3 seems to be protective in diseases such as age-related, neurodegenerative, liver, kidney, heart, and metabolic ones, as well as in cancer. In most cases, activating SIRT3 could be a promising strategy to tackle these health problems. Here, we summarize the main biological functions, substrates, and interactors of SIRT3, as well as several molecules reported in the literature that are able to modulate SIRT3 activity. Among the activators, some derive from natural products, others from library screening, and others from the classical medicinal chemistry approach

Histone deacetylase 10: A polyamine deacetylase from the crystal structure to the first inhibitors

Polyamine deacetylase activity was discovered more than 40 years ago, but the responsible histone deacetylase 10 (HDAC10) was described only recently. HDAC10 is a class IIb HDAC, as is its closest relative, the a-tubulin deacetylase HDAC6. HDAC10 has attracted attention over the last 2 years due to its role in diseases, especially cancer. This review summarises chemical and structural biology approaches to the study of HDAC10. Light will be shed on recent advances in understanding the complex structural biology of HDAC10 and the discovery of the first highly selective HDAC10 inhibitors

Application of Small Epigenetic Modulators in Pediatric Medulloblastoma

Medulloblastoma is one of the most frequent among pediatric brain tumors, and it has been classified in various subgroups. Some of them already benefit from quite good therapeutic options, whereas others urgently need novel therapeutic approaches. Epigenetic modulators have long been studied in various types of cancer. Within this review, we summarize the main preclinical studies regarding epigenetic targets (such as HDAC, SIRT, BET, EZH2, G9a, LSD1, and DNMT) inhibitors in medulloblastoma. Furthermore, we shed light on the increasing number of applications of drug combinations as well as hybrid compounds involving epigenetic mechanisms. Nevertheless, in the studies published so far, mainly un-specific or old modulators have been used, and the PKs (brain permeability) have not been well-evaluated. Thus, these findings should be considered as a starting point for further improvement and not as a final result

Amphetamine modulation of long-term object recognition memory in rats: influence of stress

Amphetamine is a potent psychostimulant that increases brain monoamine levels. Extensive evidence demonstrated that norepinephrine is crucially involved in the regulation of memory consolidation for stressful experiences. Here, we investigated amphetamine effects on the consolidation of long-term recognition memory in rats exposed to different intensities of forced swim stress immediately after training. Furthermore, we evaluated whether such effects are dependent on the activation of the peripheral adrenergic system. To this aim, male adult Sprague Dawley rats were subjected to an object recognition task and intraperitoneally administered soon after training with amphetamine (0.5 or 1 mg/kg), or its corresponding vehicle. Rats were thereafter exposed to a mild (1 min, 25 ± 1°C) or strong (5 min, 19 ± 1°C) forced swim stress procedure. Recognition memory retention was assessed 24-h after training. Our findings showed that amphetamine enhances the consolidation of memory in rats subjected to mild stress condition, while it impairs long-term memory performance in rats exposed to strong stress. These dichotomic effects is dependent on stress-induced activation of the peripheral adrenergic response

Novel inhibitors of human histone deacetylases: Design, synthesis and bioactivity of 3-alkenoylcoumarines

International audienceHistone deacetylases (HDACs) are well-established, promising targets for anticancer therapy due to their critical role in cancer development. Accordingly, an increasing number of HDAC inhibitors displaying cytotoxic effects against cancer cells have been reported. Among them, a large panel of chemical structures was described including coumarin-containing molecules. In this study, we described synthesis and biological activity of new coumarin-based derivatives as HDAC inhibitors. Among eight derivatives, three compounds showed HDAC inhibitory activities and antitumor activities against leukemia cell lines without affecting the viability of peripheral blood mononuclear cells from healthy donors

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities

GreenMedChem : the challenge in the next decade toward eco-friendly compounds and processes in drug design

Green chemistry has become a hot topic and the focus of not only many companies but also researchers. Green chemistry strives to identify alternative and environmentally friendly reaction conditions and simultaneously aims to increase the rates and reduce the temperature of reactions. Specifically, the goal of green chemistry is to reduce the impact of chemical substances and processes on human health and the effective elimination of environmental pollution through dedicated sustainable prevention programs. Green chemistry is based on innovative scientific solutions to solve environmental problems that arise in the laboratory. In this review, we analyse in detail each of the 12 Principles of Green Chemistry developed by Paul Anastas in 1991, emphasising the aspects of medicinal chemistry carried out in research laboratories for the synthesis of active pharmaceutical ingredients (API). Here, we provide some examples of greener reactions, which can substitute the older strategies carried out by both industries and academia and offer a guide to improve the greenness of reactions. The present review highlights the methods that can be used by medicinal chemists in their daily work not only to improve the yields but also to reduce and prevent pollution, thereby protecting the environment and our health

Novel Pyridine-Based Hydroxamates and 2'-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity

Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide 5b previously described by us as HDAC inhibitor, we prepared four aza-analogues of 5b (6-8, 9b) as regioisomers containing the pyridine nucleus. A preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide 9b as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9a, 9c-f, and 11a-f) and 2'-aminoanilides (10a-f and 12a-f), related to 9b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11d displayed subnanomolar potency (IC50: 0.5 nM) and selectivity up to 34000-fold over HDAC4 and from 100- to 1300-fold over all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12d being the most effective (IC50HDAC3 = 0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9e, 11c, and 11d blocked over 80% cells in G2/M phase, whereas the anilides did not alter the cell cycle progress. In the same cell line, the hydroxamate 11c and the anilide 10b induced about 30% apoptosis, and the anilide 12c displayed about 40% cytodifferentiation. Finally, the most potent compounds in leukemia cells 9b, 11c, 10b, 10e, and 12c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single-digit to sub-micromolar level

Detrimental effects of the 'bath salt' methylenedioxypyrovalerone on social play behavior in male rats

Methylenedioxypyrovalerone (MDPV) is the most popular synthetic cathinone found in products marketed as 'bath salts', widely abused among teenagers and young adults. Synthetic cathinones have pharmacological effects resembling those of psychostimulants, which are known to disrupt a variety of social behaviors. However, despite the popular use of MDPV by young people in social contexts, information about its effects on social behavior is scarce. To investigate the impact of MDPV on social behavior at young age, and the underlying neurobehavioral mechanisms, we focused on social play behavior. Social play behavior is the most characteristic social behavior displayed by young mammals and it is crucial for neurobehavioral development. Treatment with MDPV reduced social play behavior in both juvenile and young adult male rats, and its play-suppressant effect was subject to tolerance but not sensitization. As the behavioral effects of MDPV have been ascribed to dopaminergic and noradrenergic neurotransmission, and given the role of these neurotransmitters in social play, we investigated the involvement of dopamine and noradrenaline in the play-suppressant effects of MDPV. The effects of MDPV on social play were blocked by either the α2 adrenoceptor antagonist RX821002 or the dopamine receptor antagonist flupenthixol, given alone or together at sub-effective doses. In sum, MDPV selectively suppresses the most vigorous social behavior of developing rats through both noradrenergic and dopaminergic mechanisms. This study provides important preclinical evidence of the deleterious effects of MDPV on social behavior, and as such increases our understanding of the neurobehavioral effects of this popular cathinone