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Ring size changes in the development of class I HDAC inhibitors.

ABSTRACT: Five pathways involving different ring structures led to generation of fourteen thienylbenzamides (7-20) which display the structure-activity relationships of class I HDAC inhibitors. All the synthesised compounds inhibit HDAC1 and HDAC2 selectively over other isoforms and many inhibit DLD1 and HCT116 cells more effectively than a parent compound. Compounds 8 and 16 inhibit HCT116 cells by activation of the apoptosis pathway.

SUBMITTER: Cho EC

PROVIDER: S-EPMC8231390 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Discovering HDAC class II selective inhibitors by multidisciplinary approach

Project description: Not available

| S-EPMC3083574 | biostudies-literature

Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes.

Project description:Histone deacetylase (HDAC) inhibitors are promising new epi-drugs, but the presence of both class I and class II enzymes in HDAC complexes precludes a detailed elucidation of the individual HDAC functions. By using the class II-specific HDAC inhibitor MC1568, we separated class I- and class II-dependent effects and defined the roles of class II enzymes in muscle differentiation in cultured cells and in vivo. MC1568 arrests myogenesis by (i) decreasing myocyte enhancer factor 2D (MEF2D) expression, (ii) by stabilizing the HDAC4-HDAC3-MEF2D complex, and (iii) paradoxically, by inhibiting differentiation-induced MEF2D acetylation. In vivo MC1568 shows an apparent tissue-selective HDAC inhibition. In skeletal muscle and heart, MC1568 inhibits the activity of HDAC4 and HDAC5 without affecting HDAC3 activity, thereby leaving MEF2-HDAC complexes in a repressed state. Our results suggest that HDAC class II-selective inhibitors might have a therapeutic potential for the treatment of muscle and heart diseases.

| S-EPMC2693879 | biostudies-literature

Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes.

Project description: Not available

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HDACs and HDAC Inhibitors in Cancer Development and Therapy.

Project description:Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Posttranslational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling, and nuclear architecture. Histone acetylation, a well-studied posttranslational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous nonhistone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.

| S-EPMC5046688 | biostudies-other

Expression profiling comparisons of human PBMC treated with class I/IIb or class IIa HDAC inhibitors

Project description:The aim of this study was to identify differential gene expression resulting from the inhibition of class IIa HDACs in human PBMC. Human PBMC were cultured ex vivo with a mitogenic stimulus (1 ug/ml phytohemagglutinin, PHA) for 60 hours concurrent with exposure to vehicle (DMSO), vorinostat (3 uM), or TMP195 (3 uM). In addition to the whole PBMC populations, a portion of the cultures treated with DMSO or TMP195 were used for FACS purification of mutually exclusive CD3+ (T cell), CD19+ (B cell), and CD14+ (monocyte) populations. All samples were then processed for RNA extraction, labeling, and hybridization to Affymetrix arrays. Vehicle vs. vorinostat vs. TMP195 treatments in PBMC; Vehicle vs. TMP195 treatment in CD3+, CD19+ or CD14+ cells

2013-03-24 | E-GEOD-44621 | biostudies-arrayexpress

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors.

Project description:Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.

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TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms.

Project description:Enhanced proliferative signaling and loss of cell cycle regulation are essential for cancer progression. Increased mitogenic signaling through activation of the mTOR pathway, coupled with deregulation of the Cyclin D/retinoblastoma (Rb) pathway is a common feature of lymphoid malignancies, including plasmacytoma (PCT), multiple myeloma (MM), Burkitt's lymphoma (BL), and mantle cell lymphoma (MCL). Here we evaluate the synergy of pharmacologically affecting both of these critical pathways using the mTOR inhibitor sirolimus and the histone deacetylase inhibitor entinostat. A dose-matrix screening approach found this combination to be highly active and synergistic in a panel of genetically diverse human MM cell lines. Synergy and activity was observed in mouse PCT and human BL and MCL cell lines tested in vitro, as well as in freshly isolated primary MM patient samples tested ex vivo. This combination had minimal effects on healthy donor cells and retained activity when tested in a co-culture system simulating the protective interaction of cancer cells with the tumor microenvironment. Combining sirolimus with entinostat enhanced cell cycle arrest and apoptosis. At the molecular level, entinostat increased the expression of cell cycle negative regulators including CDKN1A (p21) and CDKN2A (p16), while the combination decreased critical growth and survival effectors including Cyclin D, BCL-XL, BIRC5, and activated MAPK.

| S-EPMC3969848 | biostudies-other

Expression profiling comparisons of human PBMC treated with class I/IIb or class IIa HDAC inhibitors

Project description:The aim of this study was to identify differential gene expression resulting from the inhibition of class IIa HDACs in human PBMC.

2013-03-24 | GSE44621 | GEO

Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation.

Project description:Induction of histone acetylation in the nucleus accumbens (NAc), a key brain reward region, promotes cocaine-induced alterations in gene expression. Histone deacetylases (HDACs) tightly regulate the acetylation of histone tails, but little is known about the functional specificity of different HDAC isoforms in the development and maintenance of cocaine-induced plasticity, and previous studies of HDAC inhibitors report conflicting effects on cocaine-elicited behavioral adaptations. Here we demonstrate that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, but also induced repressive histone methylation and antagonized cocaine-induced changes in behavior, an effect mediated in part through a chromatin-mediated suppression of GABAA receptor subunit expression and inhibitory tone on NAc neurons. Our findings suggest a new mechanism by which prolonged and selective HDAC inhibition can alter behavioral and molecular adaptations to cocaine and inform the development of therapeutics for cocaine addiction.

| S-EPMC3609040 | biostudies-literature

Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides.

Project description:The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compounds reported to date.

| S-EPMC6466521 | biostudies-literature

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