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https://www.readbyqxmd.com/read/28453994/synthesis-and-applications-of-benzohydroxamic-acid-based-histone-deacetylase-inhibitors
#1
REVIEW
Rob De Vreese, Matthias D'hooghe
This paper provides an overview of the synthesis and biological activity of the most representative benzohydroxamic acid-based histone deacetylase inhibitors published to date. Benzohydroxamic acids comprise an important class of HDAC inhibitors, and recently several of these structures have been evaluated in clinical trials for the treatment of a variety of cancers. In this overview, benzohydroxamic acids were divided in four different classes based on their reported selectivity towards zinc-dependent HDACs: a first and major class consists of HDAC6 selective inhibitors, a second class deals with pan-HDAC inhibitors, a third class comprises HDAC8 selective inhibitors and a fourth, minor class includes dual HDAC6/8 selective inhibitors...
April 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28447718/role-of-histone-deacetylase-expression-levels-and-activity-in-the-inflammatory-responses-of-patients-with-chronic-hepatitis-b
#2
Haiyue Zhang, Xun Li, Qian Zhang, Fan Yang, Xiaogang Chu, Di Zhang, Luwen Wang, Zuojiong Gong
Histone acetylation has been demonstrated to serve a pivotal role in numerous inflammatory diseases. The present study examined histone acetylation in patients with chronic hepatitis B (CHB) and CHB with liver failure by detecting histone deacetylase (HDAC) activity. Mice with acute liver failure (ALF) were treated with the HDAC inhibitor entinostat (MS275) and alterations in HDAC activity and pro‑inflammatory cytokine expression levels were detected. The effect of HDAC1 silencing on LPS-treated RAW264.7 murine macrophages was examined using specific small interfering RNA sequences, and the acetylation level of the non‑histone nuclear factor‑κB (NF‑κB) p65 subunit was additionally examined...
March 7, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28447074/chidamide-tablets-hdac-inhibition-to-treat-lymphoma
#3
Y Xu, P Zhang, Y Liu
Chidamide is the first oral subtype-selective histone deacetylase inhibitor (HDACI) approved in China as well as the first HDACI of the benzamide class approved for the treatment of relapsed and refractory peripheral T-cell lymphoma (PTCL). This review addresses detailed information regarding chidamide, including the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, clinical studies and application, safety, drug interactions and ongoing clinical trials. Although twice-weekly chidamide monotherapy has been recommended based on the evidence from preclinical and clinical studies with tolerable toxicities, its clinical efficacy could be further increased by combination with multidrug chemotherapy or chemo-free regimens...
March 2017: Drugs of Today
https://www.readbyqxmd.com/read/28445736/systematic-epigenomic-analysis-reveals-chromatin-states-associated-with-melanoma-progression
#4
Petko Fiziev, Kadir C Akdemir, John P Miller, Emily Z Keung, Neha S Samant, Sneha Sharma, Christopher A Natale, Christopher J Terranova, Mayinuer Maitituoheti, Samirkumar B Amin, Emmanuel Martinez-Ledesma, Mayura Dhamdhere, Jacob B Axelrad, Amiksha Shah, Christine S Cheng, Harshad Mahadeshwar, Sahil Seth, Michelle C Barton, Alexei Protopopov, Kenneth Y Tsai, Michael A Davies, Benjamin A Garcia, Ido Amit, Lynda Chin, Jason Ernst, Kunal Rai
The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways...
April 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28445158/the-hdac-inhibitor-valproate-induces-a-bivalent-status-of-the-cd20-promoter-in-cll-patients-suggesting-distinct-epigenetic-regulation-of-cd20-expression-in-cll-in-vivo
#5
Annarita Scialdone, Muhammad Sharif Hasni, Jesper Kofoed Damm, Andreas Lennartsson, Urban Gullberg, Kristina Drott
Treatment with anti-CD20 antibodies is only moderately efficient in chronic lymphocytic leukemia (CLL), a feature which has been explained by the inherently low CD20 expression in CLL. It has been shown that CD20 is epigenetically regulated and that histone deacetylase inhibitors (HDACis) can increase CD20 expression in vitro in CLL. To assess whether HDACis can upregulate CD20 also in vivo in CLL, the HDACi valproate was given to three del13q/NOTCH1wt CLL patients and CD20 levels were analysed (the PREVAIL study)...
April 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28440559/a-phase-2-study-of-mocetinostat-a-histone-deacetylase-inhibitor-in-relapsed-or-refractory-lymphoma
#6
Connie L Batlevi, Michael Crump, Charalambos Andreadis, David Rizzieri, Sarit E Assouline, Susan Fox, Richard H C van der Jagt, Amanda Copeland, Diane Potvin, Richard Chao, Anas Younes
Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31)...
April 25, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28440397/hypermethylation-of-mirna-589-promoter-leads-to-upregulation-of-hdac5-which-promotes-malignancy-in-non-small-cell-lung-cancer
#7
Changhong Liu, Desheng Lv, Mo Li, Xuefei Zhang, Ge Sun, Yu Bai, Dongmin Chang
Histone deacetylases (HDACs) are crucial for regulating chromatin activity, which plays a critical role in cell proliferation, differentiation, and apoptosis of various cancers. Therefore, HDAC inhibitors have been applied as effective therapeutic agents for cancer treatment. However, the expression profiles and regulatory mechanisms of histone deacetylases in lung cancer are not well understood. In the present study, aberrant high levels of HDAC5 were observed in non-small cell lung cancer (NSCLC) and further analysis indicated a negative relationship between HDAC5 and a tumor suppressor, miR‑589‑5p, in NSCLC specimens...
April 20, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28434841/transcriptional-dependencies-in-diffuse-intrinsic-pontine-glioma
#8
Surya Nagaraja, Nicholas A Vitanza, Pamelyn J Woo, Kathryn R Taylor, Fang Liu, Lei Zhang, Meng Li, Wei Meng, Anitha Ponnuswami, Wenchao Sun, Jie Ma, Esther Hulleman, Tomek Swigut, Joanna Wysocka, Yujie Tang, Michelle Monje
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade...
April 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28433417/mechanistic-insights-into-epigenetic-modulation-of-ethanol-consumption
#9
Igor Ponomarev, Claire E Stelly, Hitoshi Morikawa, Yuri A Blednov, R Dayne Mayfield, R Adron Harris
There is growing evidence that small-molecule inhibitors of epigenetic modulators, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), can reduce voluntary ethanol consumption in animal models, but molecular and cellular processes underlying this behavioral effect are poorly understood. We used C57BL/6J male mice to investigate the effects of two FDA-approved drugs, decitabine (a DNMT inhibitor) and SAHA (an HDAC inhibitor), on ethanol consumption using two tests: binge-like drinking in the dark (DID) and chronic intermittent every other day (EOD) drinking...
March 12, 2017: Alcohol
https://www.readbyqxmd.com/read/28431939/modulation-of-hat-activity-by-the-brca2n372hvariation-is-a-novel-mechanism-of-paclitaxel-resistance-in-breast-cancer-cell-lines
#10
Woo Sun Kwon, Sun Young Rha, Hei-Cheul Jeung, Tae Soo Kim, Hyun Cheol Chung
Paclitaxel stabilizes microtubule polymerization, enhances microtubule assembly, andG2/M arrests, leading to cell death. Paclitaxel resistance has been attributed to a variety of mechanisms. In the present study, we define a new resistance mechanism to paclitaxel based onBRCA2variation. Chemo-sensitivity to paclitaxel based on the variations was compared. Restoration of paclitaxel sensitivity was induced indirectly with combined treatment of paclitaxel and HDAC inhibitor. Variant and wild type of BRCA2 clones were obtained from wild and variant cells, respectively...
April 18, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28429765/repolarizing-macrophages-improves-breast-cancer-therapy
#11
Luca Cassetta, Jeffrey W Pollard
Tumor-associated macrophages (TAMs) contribute to breast cancer progression and dissemination; TAM-targeting strategies aimed at their reprogramming show promising preclinical results. In a new report Guerriero and colleagues demonstrate that a novel HDAC Class IIa inhibitor, TMP195, can reprogram monocytes and macrophages in the tumor into cells able to sustain a robust CD8 T cell-mediated anti-tumoral immune response.
April 21, 2017: Cell Research
https://www.readbyqxmd.com/read/28426972/unlocking-the-chromatin-of-adenoid-cystic-carcinomas-using-hdac-inhibitors-sensitize-cancer-stem-cells-to-cisplatin-and-induces-tumor-senescence
#12
Luciana O Almeida, Douglas M Guimarães, Manoela D Martins, Marco A T Martins, Kristy A Warner, Jacques E Nör, Rogerio M Castilho, Cristiane H Squarize
No abstract text is available yet for this article.
April 8, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28425177/design-and-synthesis-of-c3-substituted-%C3%AE-carboline-based-histone-deacetylase-inhibitors-with-potent-antitumor-activities
#13
Yong Ling, Jiao Feng, Lin Luo, Jing Guo, Yanfu Peng, Tingting Wang, Xiang Ge, Qibing Xu, Xinyang Wang, Hong Dai, Yanan Zhang
A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β-carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was investigated. Most of these compounds were found to display significant HDAC inhibitory effects and good antiproliferative activity, with IC50 values in the low-micromolar range. In particular, the HDAC inhibition IC50 value of N-(2-(dimethylamino)ethyl)-N-(4-(hydroxylcarbamoyl)benzyl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (9 h) is five-fold lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat)...
April 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28421257/histone-deacetylase-inhibitors-reverse-age-related-increases-in-side-effects-of-haloperidol-in-mice
#14
Janitza L Montalvo-Ortiz, Daniel W Fisher, Guadalupe Rodríguez, Deyu Fang, John G Csernansky, Hongxin Dong
BACKGROUND: Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. METHODS: In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects...
April 18, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28420416/emerging-therapies-for-acute-myeloid-leukemia
#15
REVIEW
Caner Saygin, Hetty E Carraway
Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28419930/design-synthesis-and-anticancer-potential-of-nsc-319745-hydroxamic-acid-derivatives-as-dnmt-and-hdac-inhibitors
#16
Zigao Yuan, Qinsheng Sun, Dan Li, Shuangshuang Miao, Shaopeng Chen, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are important epigenetic targets during anticancer drug development. Recent study indicates that DNMT inhibitors and HDAC inhibitors display synergistic effects in certain cancers, therefore, development of molecules targeting both DNMT and HDAC is of therapeutic advantage against these cancers. Based on the structure of DNMT inhibitor NSC-319745 and the pharmacophore characteristics of HDAC inhibitors, a series of hydroxamic acid derivatives of NSC-319745 were designed and synthesized as DNMT and HDAC multifunctional inhibitors...
April 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28418886/histone-hypoacetylation-contributes-to-cxcl12-downregulation-in-colon-cancer-impact-on-tumor-growth-and-cell-migration
#17
Benoît Romain, Radhia Benbrika-Nehmar, Laetitia Marisa, Michèle Legrain, Viviane Lobstein, Attila Oravecz, Laetitia Poidevin, Cyril Bour, Jean-Noël Freund, Isabelle Duluc, Dominique Guenot, Erwan Pencreach
CXCL12 has been shown to be involved in colon cancer metastasis, but its expression level and molecular mechanisms regulating its expression remain controversial. We thus evaluated CXCL12 expression in a large cohort of colon adenomas and carcinomas, investigated for an epigenetic mechanism controlling its expression and evaluated the impact of CXCL12 levels on cell migration and tumor growth. CXCL12 expression was measured in human colon adenomas and carcinomas with transcriptome array and RT-qPCR. The promoter methylation was analyzed with whole-genome DNA methylation chips and protein expression by immunohistochemistry...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416766/notch3-overexpression-enhances-progression-and-chemoresistance-of-urothelial-carcinoma
#18
Heng Zhang, Limei Liu, Chungang Liu, Jinhong Pan, Gensheng Lu, Zhansong Zhou, Zhiwen Chen, Cheng Qian
Abnormal activation of Notch signaling is involved in the etiology of various diseases, including cancer, but the association between Notch3 expression in urothelial cancer and clinical outcome remains unclear, and the molecular mechanisms underlying Notch3 signaling activation are not well defined. In this study we examined 59 urothelial cancer patients and found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression being associated with poor clinical outcome...
March 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416758/synergistic-interactions-between-plk1-and-hdac-inhibitors-in-non-hodgkin-s-lymphoma-cells-occur-in-vitro-and-in-vivo-and-proceed-through-multiple-mechanisms
#19
Tri Nguyen, Rebecca Parker, Elisa Hawkins, Beata Holkova, Victor Yazbeck, Akhil Kolluri, Maciej Kmieciak, Mohamed Rahmani, Steven Grant
Interactions between the polo-like kinase 1 (PLK1) inhibitor volasertib and the histone deacetylase inhibitor (HDACI) belinostat were examined in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells in vitro and in vivo. Exposure of DLBCL cells to very low concentrations of volasertib in combination with belinostat synergistically increased cell death (apoptosis). Similar interactions occurred in GC-, ABC-, double-hit DLBCL cells, MCL cells, bortezomib-resistant cells and primary lymphoma cells...
February 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416226/klotho-restoration-via-acetylation-of-peroxisome-proliferation-activated-receptor-%C3%AE-reduces-the-progression-of-chronic-kidney-disease
#20
Wenjun Lin, Qin Zhang, Lin Liu, Shasha Yin, Zhihong Liu, Wangsen Cao
Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho (1) expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation-Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A...
April 14, 2017: Kidney International
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