Publications by authors named "Antonello Mai"

267 Publications

A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression.

Int J Antimicrob Agents 2022 Jan 15:106526. Epub 2022 Jan 15.

Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France. Electronic address:

Toxoplasmosis is a major health issue worldwide especially for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii. Although the drugs commonly used to treat toxoplasmosis are efficient, they present serious side effects and adverse events are common. Therefore, there is a need for the discovery of new compounds with potent anti-T. gondii activity. We have tested compounds designed to target enzymes that are involved in the epigenetic regulation of gene expression. Among the most active compounds, we identified an HDAC inhibitor that shows an IC of around 30 nM with a selectivity index of more than 100. MC1742 is active at inhibiting the growth of the parasite in vitro but also at preventing the consequences of the acute disease in vivo. This compound induces hyper-acetylation of histones while acetylated tubulin level remains unchanged. After MC1742 treatment, the parasite expression profile is profoundly changed with the activation of genes preferentially expressed in the sexual stages that are normally repressed at the tachyzoite stage. These findings suggest that this compound disturbs the T. gondii gene expression program, inducing parasite death.
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http://dx.doi.org/10.1016/j.ijantimicag.2022.106526DOI Listing
January 2022

Sex-dependent Effects of the Drugs of Abuse Amphetamine and the Smart Drug 3,4-Methylenedioxypyrovalerone on Fear Memory Generalization in Rats.

Neuroscience 2021 Dec 27. Epub 2021 Dec 27.

Dept. of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy; European Center for Brain Research (CERC), Santa Lucia Foundation, 00143 Rome, Italy. Electronic address:

In recent years there has been an increase in the development of new synthetic drugs, among which the "bath salt" 3,4-methylenedioxypyrovalerone (MDPV), a psychostimulant with a mechanism of action similar to those of cocaine and amphetamine, stands out. Drugs of abuse have been consistently shown to affect memory function in male rodents. We have recently shown that amphetamine and MDPV induce generalization of fear memory in an inhibitory avoidance discrimination task in male rats. Although abuse of illicit drugs is more prevalent in men than in women, several studies have demonstrated that females are more vulnerable to the effects of drugs of abuse than males and the effects caused by substance dependence on memory in females are still under-investigated. Thus, we examined the effects of subchronic amphetamine or MDPV administrations on memory in a contextual fear conditioning/generalization paradigm in adult male and female rats. Animals were given daily subchronic injections of the drugs, starting 6 days prior to the beginning of the behavioral procedures until the end of the paradigm. On day 1 of the experimental protocol, all rats were exposed to a safe context and, the day after, to a slightly different chamber where they received an unsignaled footshock. Twenty-four and forty-eight hours later, freezing behavior and emission of 22 kHz-ultrasonic vocalizations (USVs) were measured in the two different contexts to assess fear memory retention and generalization. Our results indicate that MDPV treatment altered freezing in both sexes, USVs were affected by amphetamine in males while by MDPV in females. This article is part of a Special Issue entitled: SI: memory of Ivan Izquierd.
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http://dx.doi.org/10.1016/j.neuroscience.2021.12.027DOI Listing
December 2021

First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53.

J Med Chem 2021 12 29;64(23):17031-17050. Epub 2021 Nov 29.

Department of Chemistry and Technology of Drugs, ″Sapienza″ University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.

MINA53 is a JmjC domain 2-oxoglutarate-dependent oxygenase that catalyzes ribosomal hydroxylation and is a target of the oncogenic transcription factor -MYC. Despite its anticancer target potential, no small-molecule MINA53 inhibitors are reported. Using ribosomal substrate fragments, we developed mass spectrometry assays for MINA53 and the related oxygenase NO66. These assays enabled the identification of 2-(aryl)alkylthio-3,4-dihydro-4-oxoypyrimidine-5-carboxylic acids as potent MINA53 inhibitors, with selectivity over NO66 and other JmjC oxygenases. Crystallographic studies with the JmjC demethylase KDM5B revealed active site binding but without direct metal chelation; however, molecular modeling investigations indicated that the inhibitors bind to MINA53 by directly interacting with the iron cofactor. The MINA53 inhibitors manifest evidence for target engagement and selectivity for MINA53 over KDM4-6. The MINA53 inhibitors show antiproliferative activity with solid cancer lines and sensitize cancer cells to conventional chemotherapy, suggesting that further work investigating their potential in combination therapies is warranted.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667043PMC
December 2021

Mass spectrometry enables the discovery of inhibitors of an LPS transport assembly disruption of protein-protein interactions.

Chem Commun (Camb) 2021 Oct 14;57(82):10747-10750. Epub 2021 Oct 14.

Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, OX1 3QZ, UK.

We developed a native mass spectrometry-based approach to quantify the monomer-dimer equilibrium of the LPS transport protein LptH. We use this method to assess the potency and efficacy of an antimicrobial peptide and small molecule disruptors, obtaining new information on their structure-activity relationships. This approach led to the identification of quinoline-based hit compounds representing the basis for the development of novel LPS transport inhibitors.
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http://dx.doi.org/10.1039/d1cc04186jDOI Listing
October 2021

Anti-influenza A virus activity and structure-activity relationship of a series of nitrobenzoxadiazole derivatives.

J Enzyme Inhib Med Chem 2021 Dec;36(1):2128-2138

Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.

Influenza viruses represent a major threat to human health and are responsible for seasonal epidemics, along with pandemics. Currently, few therapeutic options are available, with most drugs being at risk of the insurgence of resistant strains. Hence, novel approaches targeting less explored pathways are urgently needed. In this work, we assayed a library of nitrobenzoxadiazole derivatives against the influenza virus A/Puerto Rico/8/34 H1N1 (PR8) strain. We identified three promising 4-thioether substituted nitrobenzoxadiazoles (, , and ) that were able to inhibit viral replication at low micromolar concentrations in two different infected cell lines using a haemagglutination assay. We further assessed these molecules using an In-Cell Western assay, which confirmed their potency in the low micromolar range. Among the three molecules, and displayed the most favourable profile of activity and selectivity and were selected as hit compounds for future optimisation studies.
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http://dx.doi.org/10.1080/14756366.2021.1982932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480593PMC
December 2021

Polycomb Repressive Complex 2 Modulation through the Development of EZH2-EED Interaction Inhibitors and EED Binders.

J Med Chem 2021 08 5;64(16):11774-11797. Epub 2021 Aug 5.

Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.

Epigenetics is nowadays a well-accepted area of research. In the last years, tremendous progress was made regarding molecules targeting EZH2, directly or indirectly. Recently tazemetostat hit the market after FDA-approval for the treatment of lymphoma. However, the impairment of EZH2 activity by orthosteric intervention has proven to be effective only in a limited subset of cancers. Considering the multiproteic nature of the PRC2 complex and the marked dependence of EZH2 functions on the other core subunits such as EED, in recent years, a new targeting approach ascended to prominence. The possibility to cripple the function of the PRC2 complex by interfering with its multimeric integrity fueled the interest in developing EZH2-EED protein-protein interaction and EED inhibitors as indirect modulators of PRC2-dependent methyltransferase activity. In this Perspective, we aim to summarize the latest findings regarding the development and the biological activity of these emerging classes of PRC2 modulators from a medicinal chemist's viewpoint.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404197PMC
August 2021

Histone-deacetylase 8 drives the immune response and the growth of glioma.

Glia 2021 Nov 26;69(11):2682-2698. Epub 2021 Jul 26.

Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.

Many epigenetic modifications occur in glioma, in particular the histone-deacetylase class proteins play a pivotal role in glioma development, driving the proliferation rate and the invasiveness of tumor cells, and modulating the tumor microenvironment. In this study, we evaluated the role of the histone deacetylase HDAC8 in the regulation of the immune response in glioma and tumor growth. We found that inhibition of HDAC8 by the specific inhibitor PCI-34051 reduces tumor volume in glioma mouse models. We reported that HDAC8 modulates the viability and the migration of human and murine glioma cells. Interestingly, HDAC8 inhibition increases the acetylation of alpha-tubulin, suggesting this epigenetic modification controls glioma migration. Furthermore, we identify HDAC8 as a key molecule that supports a poorly immunogenic tumor microenvironment, modulating microglial phenotype and regulating the gene transcription of NKG2D ligands that trigger the Natural Killer cell-mediated cytotoxicity of tumor cells. Altogether, these results identify HDAC8 as a key actor in glioma growth and tumor microenvironment, and pave the way to a better knowledge of the molecular mechanisms of immune escape in glioma.
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http://dx.doi.org/10.1002/glia.24065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457175PMC
November 2021

Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.

Gastroenterology 2021 11 8;161(5):1584-1600. Epub 2021 Jul 8.

Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.

Background & Aims: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown.

Methods: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts.

Results: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine.

Conclusions: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
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http://dx.doi.org/10.1053/j.gastro.2021.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546779PMC
November 2021

Emerging Therapeutic Potential of SIRT6 Modulators.

J Med Chem 2021 07 2;64(14):9732-9758. Epub 2021 Jul 2.

Department of Drug Chemistry & Technologies, Sapienza University of Rome, P.le A Moro 5, 00185 Rome, Italy.

Sirtuin 6 (SIRT6) is an NAD-dependent protein deacylase and mono-ADP-ribosyltransferase of the sirtuin family with a wide substrate specificity. and studies have indicated that SIRT6 overexpression or activation has beneficial effects for cellular processes such as DNA repair, metabolic regulation, and aging. On the other hand, SIRT6 has contrasting roles in cancer, acting either as a tumor suppressor or promoter in a context-specific manner. Given its central role in cellular homeostasis, SIRT6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing a therapeutic potential in diseases ranging from cancer to age-related disorders. Moreover, specific modulators allow the molecular details of SIRT6 activity to be scrutinized and further validate the enzyme as a pharmacological target. In this Perspective, we summarize the current knowledge about SIRT6 pharmacology and medicinal chemistry and describe the features of the activators and inhibitors identified so far.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389836PMC
July 2021

SIRT5 Inhibition Induces Brown Fat-Like Phenotype in 3T3-L1 Preadipocytes.

Cells 2021 05 7;10(5). Epub 2021 May 7.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00163 Rome, Italy.

Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. The activation of BAT results in increased energy expenditure, making this tissue an attractive pharmacological target for therapies against obesity and type 2 diabetes. Sirtuin 5 (SIRT5) affects BAT function by regulating adipogenic transcription factor expression and mitochondrial respiration. We analyzed the expression of SIRT5 in the different adipose depots of mice. We treated 3T3-L1 preadipocytes and mouse primary preadipocyte cultures with the SIRT5 inhibitor MC3482 and investigated the effects of this compound on adipose differentiation and function. The administration of MC3482 during the early stages of differentiation promoted the expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed an increased activation of the AMP-activated protein kinase (AMPK), which is known to stimulate brown adipocyte differentiation. This effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size, mediated by a higher lipolytic rate. Of note, MC3482 increased the expression and the activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro, supporting this approach as a strategy to stimulate BAT and counteract obesity.
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http://dx.doi.org/10.3390/cells10051126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148511PMC
May 2021

The Two-Faced Role of SIRT6 in Cancer.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

Department of Drug Chemistry & Technologies, Sapienza University of Rome, P. le A Moro 5, 00185 Rome, Italy.

Sirtuin 6 (SIRT6) is a NAD-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic homeostasis, and apoptosis. SIRT6 regulates the expression and activity of both pro-apoptotic (e.g., Bax) and anti-apoptotic factors (e.g., Bcl-2, survivin) in a context-depending manner. Mounting evidence points towards a double-faced involvement of SIRT6 in tumor onset and progression since the block or induction of apoptosis lead to opposite outcomes in cancer. Here, we discuss the features and roles of SIRT6 in the regulation of cell death and cancer, also focusing on recently discovered small molecule modulators that can be used as chemical probes to shed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics.
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http://dx.doi.org/10.3390/cancers13051156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962659PMC
March 2021

Amphetamine Modulation of Long-Term Object Recognition Memory in Rats: Influence of Stress.

Front Pharmacol 2021 24;12:644521. Epub 2021 Feb 24.

Dept. of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.

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.
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http://dx.doi.org/10.3389/fphar.2021.644521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943736PMC
February 2021

Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer.

Cancers (Basel) 2021 Feb 1;13(3). Epub 2021 Feb 1.

Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy.

The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.
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http://dx.doi.org/10.3390/cancers13030543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867078PMC
February 2021

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

ChemMedChem 2021 03 16;16(6):989-999. Epub 2020 Dec 16.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 500185, Rome, Italy.

Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6-8, 9 b, as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide (9 b) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9 a, 9 c-f, and 11 a-f) and 2'-aminoanilides (10 a-f and 12 a-f), related to 9 b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC : 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC =0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e, 11 c, and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b, 11 c, 10 b, 10 e, and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC values at single-digit to sub-micromolar level.
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http://dx.doi.org/10.1002/cmdc.202000854DOI Listing
March 2021

Downregulation of miR-326 and its host gene β-arrestin1 induces pro-survival activity of E2F1 and promotes medulloblastoma growth.

Mol Oncol 2021 02 31;15(2):523-542. Epub 2020 Dec 31.

Department of Experimental Medicine, Sapienza University, Rome, Italy.

Persistent mortality rates of medulloblastoma (MB) and severe side effects of the current therapies require the definition of the molecular mechanisms that contribute to tumor progression. Using cultured MB cancer stem cells and xenograft tumors generated in mice, we show that low expression of miR-326 and its host gene β-arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro-survival function. Our models revealed that miR-326 and ARRB1 are controlled by a bivalent domain, since the H3K27me3 repressive mark is found at their regulatory region together with the activation-associated H3K4me3 mark. High levels of EZH2, a feature of MB, are responsible for the presence of H3K27me3. Ectopic expression of miR-326 and ARRB1 provides hints into how their low levels regulate E2F1 activity. MiR-326 targets E2F1 mRNA, thereby reducing its protein levels; ARRB1, triggering E2F1 acetylation, reverses its function into pro-apoptotic activity. Similar to miR-326 and ARRB1 overexpression, we also show that EZH2 inhibition restores miR-326/ARRB1 expression, limiting E2F1 pro-proliferative activity. Our results reveal a new regulatory molecular axis critical for MB progression.
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http://dx.doi.org/10.1002/1878-0261.12800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858128PMC
February 2021

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas.

Front Pharmacol 2020 13;11:1230. Epub 2020 Aug 13.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.

Cyclin-Dependent Kinases (CDKs) are well-known reliable targets for cancer treatment being often deregulated. Among them, since the transcription-associated CDK9 represents the sentry of cell transcriptional homeostasis, it can be a valuable target for managing cancers in which the transcriptional machinery is dysregulated by tumor-driver oncogenes. Here we give an overview of some natural compounds identified as CDK inhibitors with reported activity also against CDK9, that were taken as a model for the development of highly active synthetic anti-CDK9 agents. After, we summarize the data on CDK9 inhibition in a group of rare pediatric solid tumors such as rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma and malignant rhabdoid tumors (soft tissue sarcomas), highlighting the more recent results in this field. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.
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http://dx.doi.org/10.3389/fphar.2020.01230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438590PMC
August 2020

Lysine Acetyltransferase Inhibitors From Natural Sources.

Front Pharmacol 2020 12;11:1243. Epub 2020 Aug 12.

Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy.

Acetylation of histone and non-histone protein lysine residues has been widely described as a critical modulator of several cell functions in humans. Lysine acetyltransferases (KATs) catalyse the transfer of acetyl groups on substrate proteins and are involved in multiple physiological processes such as cell signalling, metabolism, gene regulation, and apoptosis. Given the pivotal role of acetylation, the alteration of KATs enzymatic activity has been clearly linked to various cellular dysfunctions leading to several inflammatory, metabolic, neurological, and cancer diseases. Hence, the use KAT inhibitors (KATi) has been suggested as a potentially successful strategy to reverse or prevent these conditions. To date, only a few KATi have proven to be potential drug candidates, and there is still a keen interest in designing molecules showing drug-like properties from both pharmacodynamics and pharmacokinetics point of view. Increasing literature evidence has been highlighting natural compounds as a wide source of molecular scaffolds for developing therapeutic agents, including KATi. In fact, several polyphenols, catechins, quinones, and peptides obtained from natural sources (including nuts, oils, root extracts, and fungi metabolites) have been described as promising KATi. Here we summarize the features of this class of compounds, describing their modes of action, structure-activity relationships and (semi)-synthetic derivatives, with the aim of assisting the development of novel more potent, isoform selective and drug-like KATi.
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http://dx.doi.org/10.3389/fphar.2020.01243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434864PMC
August 2020

Recent advances in epigenetic proteolysis targeting chimeras (Epi-PROTACs).

Eur J Med Chem 2020 Dec 18;207:112750. Epub 2020 Aug 18.

Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, 00185, Rome, Italy. Electronic address:

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules that trigger the poly-ubiquitination of the protein of interest (POI) inducing its degradation via the recruitment of the ubiquitin-proteasome system, thus suppressing the POI's intracellular levels and indirectly all its functions. Recently, one of the fields where the protein knockdown induced by PROTACs has demonstrated to serve as a promising biochemical tool and to provide new opportunities for drug discovery is the epigenetics (epi-PROTACs). A full inhibition of the functions of all domains of a specific epigenetic POI (e-POI), rather than just the block of its catalytic/single domain activity, is in fact a new more effective modality to hit an e-POI and, in principle, the complex it belongs to, and potentially to treat the related diseases, first cancer. In this review, we will present the most relevant progresses made, especially in the last two years, in the application of PROTACs technology to the three main classes of e-POIs: "writers", "erasers" and "readers". Emphasis will be devoted to the medicinal chemistry aspects of the epi-PROTACs design, preparation, and optimization and to the comparison with small molecule epi-drugs for both epi-targets functional annotation and potential anticancer therapy purposes.
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http://dx.doi.org/10.1016/j.ejmech.2020.112750DOI Listing
December 2020

Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells.

Molecules 2020 Jul 8;25(14). Epub 2020 Jul 8.

Dipartimento di Chimica e Tecnologie del Farmaco, 'Sapienza' Università di Roma, 00185 Roma, Italy.

Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis(()-3-bromobenzylidene)piperidin-4-one displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis(()-2-bromobenzylidene) cyclic compounds - to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of - exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (), benzyl (), or acyl (-) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl () and 3-phenylpropyl () decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (-). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.
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http://dx.doi.org/10.3390/molecules25143122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397249PMC
July 2020

The Innovative Potential of Statins in Cancer: New Targets for New Therapies.

Front Chem 2020 18;8:516. Epub 2020 Jun 18.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.

Numerous and different types of cancers possess the dysregulation of the mevalonate pathway as a common feature. Statins, traditionally applied in cardiovascular diseases to reduce lipid levels, subsequently have been discovered to exhibit anti-cancer activities also. Indeed, statins influence proliferation, migration, and survival of cancer cells by regulating crucial signaling proteins, such as Rho, Ras, and Rac. Recently, several studies have demonstrated that simvastatin, fluvastatin, and lovastatin are implicated in different pathways that enhance the survival time of patients with cancer under treatment in combination with antineoplastic agents. In this minireview, we present an overview of the most important studies conducted regarding the use of statins in cancer therapy up to date.
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http://dx.doi.org/10.3389/fchem.2020.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312214PMC
June 2020

Targeting histone acetylation/deacetylation in parasites: an update (2017-2020).

Curr Opin Chem Biol 2020 08 29;57:65-74. Epub 2020 Jun 29.

Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address:

Histone modifying enzymes have vital roles in the growth and survival of both parasites and humans. Targeting the epigenome can be a new strategy for the treatment of parasitic diseases. Compounds modulating histone acetylation/deacetylation have recently been reported hampering Plasmodium, Schistosoma, Leishmania, and Trypanosoma infections. Beside new histone deacetylase inhibitors, PfGCN5 and bromodomain inhibitors have been recently described to inhibit Plasmodium proliferation. Sm histone deacetylase 8 and SmSIRT2, as well as Leishmania and Trypanosoma sirtuins (SIR2rps), seem to be the most reliable targets to effectively fight the related protozoan infections. The selectivity toward parasite over mammalian cells is still an open question, and significant optimization efforts of epidrugs are still required to improve potency/selectivity and decrease toxicity. Recent reports on the alteration of cellular signaling pathways provoked by parasite infection through changes in the host acetylation/deacetylation status at gene promoters may suggest novel therapeutic strategies to treat these diseases.
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http://dx.doi.org/10.1016/j.cbpa.2020.05.008DOI Listing
August 2020

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni.

PLoS Negl Trop Dis 2020 07 1;14(7):e0008332. Epub 2020 Jul 1.

Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.
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http://dx.doi.org/10.1371/journal.pntd.0008332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329083PMC
July 2020

The Pan-Sirtuin Inhibitor MC2494 Regulates Mitochondrial Function in a Leukemia Cell Line.

Front Oncol 2020 21;10:820. Epub 2020 May 21.

Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.

The involvement of sirtuins (SIRTs) in modulating metabolic and stress response pathways is attracting growing scientific interest. Some SIRT family members are located in mitochondria, dynamic organelles that perform several crucial functions essential for eukaryotic life. Mitochondrial dysfunction has emerged as having a key role in a number of human diseases, including cancer. Here, we investigated mitochondrial damage resulting from treatment with a recently characterized pan-SIRT inhibitor, MC2494. MC2494 was able to block mitochondrial biogenesis and function in terms of ATP synthesis and energy metabolism, suggesting that it might orchestrate cell response to metabolic stress and thereby interfere with cancer promotion and progression. Targeting mitochondrial function could thus be considered a potential anticancer strategy for use in clinical therapy.
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http://dx.doi.org/10.3389/fonc.2020.00820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255067PMC
May 2020

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

Neuropsychopharmacology 2020 11 7;45(12):2012-2019. Epub 2020 Jun 7.

Department of Science, University "Roma Tre", Rome, Italy.

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.
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http://dx.doi.org/10.1038/s41386-020-0729-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547114PMC
November 2020

Diphenylene Iodonium Is a Noncovalent MAO Inhibitor: A Biochemical and Structural Analysis.

ChemMedChem 2020 08 10;15(15):1394-1397. Epub 2020 Jun 10.

Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.

Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin- and heme-dependent enzymes, and is often used as an NADPH oxidase inhibitor. We probed the efficacy of DPI on two well-known drug targets, the human monoamine oxidases MAO A and B. UV-visible spectrophotometry and steady-state kinetics experiments demonstrate that DPI acts as a competitive and reversible MAO inhibitor with K values of 1.7 and 0.3 μM for MAO A and MAO B, respectively. Elucidation of the crystal structure of human MAO B bound to the inhibitor revealed that DPI binds deeply in the active-site cavity to establish multiple hydrophobic interactions with the surrounding side chains and the flavin. These data prove that DPI is a genuine MAO inhibitor and that the inhibition mechanism does not involve a reaction with the reduced flavin. This binding and inhibitory activity against the MAOs, two major reactive oxygen species (ROS)-producing enzymes, will have to be carefully considered when interpreting experiments that rely on DPI for target validation and chemical biology studies on ROS functions.
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http://dx.doi.org/10.1002/cmdc.202000264DOI Listing
August 2020

Identification of Inhibitors to Sirtuins Based on Compounds Developed to Human Enzymes.

Int J Mol Sci 2020 May 22;21(10). Epub 2020 May 22.

Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039032, SP, Brazil.

Chagas disease is an illness caused by the protozoan parasite , affecting more than 7 million people in the world. Benznidazole and nifurtimox are the only drugs available for treatment and in addition to causing several side effects, are only satisfactory in the acute phase of the disease. Sirtuins are NAD-dependent deacetylases involved in several biological processes, which have become drug target candidates in various disease settings. presents two sirtuins, one cytosolic (TcSir2rp1) and the latter mitochondrial (TcSir2rp3). Here, we characterized the effects of human sirtuin inhibitors against sirtuins as an initial approach to develop specific parasite inhibitors. We found that, of 33 compounds tested, two inhibited TcSir2rp1 ( and ), while other five inhibited TcSir2rp3 (, , , , and ), indicating that specific inhibitors can be devised for each one of the enzymes. Furthermore, all inhibiting compounds prevented parasite proliferation in cultured mammalian cells. When combining the most effective inhibitors with benznidazole at least two compounds, and , demonstrated synergistic effects. Altogether, these results support the importance of exploring sirtuins as drug targets and provide key elements to develop specific inhibitors for these enzymes as potential targets for Chagas disease treatment.
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http://dx.doi.org/10.3390/ijms21103659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279216PMC
May 2020

Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells.

ACS Med Chem Lett 2020 May 19;11(5):977-983. Epub 2020 Mar 19.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.

Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed the first-in-class dual EZH2/HDAC inhibitor displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, the hybrid impaired cell viability at low micromolar level and in leukemia U937 and rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, and increased differentiation, associated with an increase of acetyl-H3 and acetyl-α-tubulin and a decrease of H3K27me3 levels. In glioblastoma U87 cells, hampered epithelial to mesenchymal transition by increasing the E-cadherin expression, thus proposing itself as a useful candidate for anticancer therapy.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236245PMC
May 2020

From PARP1 to TNKS2 Inhibition: A Structure-Based Approach.

ACS Med Chem Lett 2020 May 3;11(5):862-868. Epub 2020 Feb 3.

Department of Chemistry and Technology of Drugs, ″Sapienza" University of Rome, 00185 Rome, Italy.

Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236224PMC
May 2020

Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer.

Front Oncol 2020 15;10:474. Epub 2020 Apr 15.

Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, Rome, Italy.

Sirtuins are NAD-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases.
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http://dx.doi.org/10.3389/fonc.2020.00474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177044PMC
April 2020
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