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Histone deacetylase (HDAC) inhibitors

Meng-Yi Xu, Albert H C Wong
Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing...
March 22, 2018: Acta Pharmacologica Sinica
Jesse J McClure, Xiaoyang Li, C James Chou
Since the identification and cloning of human histone deacetylases (HDACs) and the rapid approval of vorinostat (Zolinza®) for the treatment of cutaneous T-cell lymphoma, the field of HDAC biology has met many initial successes. However, many challenges remain due to the complexity involved in the lysine posttranslational modifications, epigenetic transcription regulation, and nonepigenetic cellular signaling cascades. In this chapter, we will: review the discovery of the first HDAC inhibitor and present discussion regarding the future of next-generation HDAC inhibitors, give an overview of different classes of HDACs and their differences in lysine deacylation activity, discuss different classes of HDAC inhibitors and their HDAC isozyme preferences, and review HDAC inhibitors' preclinical studies, their clinical trials, their pharmacokinetic challenges, and future direction...
2018: Advances in Cancer Research
Obdulia Rabal, Juan A Sánchez-Arias, Mar Cuadrado-Tejedor, Irene de Miguel, Marta Pérez-González, Carolina García-Barroso, Ana Ugarte, Ander Estella-Hermoso de Mendoza, Elena Sáez, Maria Espelosin, Susana Ursua, Tan Haizhong, Wu Wei, Xu Musheng, Ana Garcia-Osta, Julen Oyarzabal
We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors...
March 14, 2018: European Journal of Medicinal Chemistry
Lianbin Yao, Sten Ohlson, Brian W Dymock
Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90)...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Li Huang, Wei-Hong Lai, Lei Zhu, Wei Li, Lei Wei, Kuo-Hsiung Lee, Lan Xie, Chin-Ho Chen
We have previously reported gnidimacrin (GM), a protein kinase C (PKC) agonist, significantly reduces the frequency of HIV-1 latently infected cells in peripheral blood mononuclear cells (PBMCs) from patients undergoing successful antiretroviral therapy at low picomolar concentrations ex vivo , which is distinct from other latency reversing agents. In this study, we demonstrate that strong viral reactivation by GM is a mechanism for elimination of latently infected cells, and a histone deacetylase inhibitor (HDACI), a thiophenyl benzamide (TPB), further potentiated the efficacy of GM against latent HIV-1...
March 8, 2018: ACS Medicinal Chemistry Letters
Mariarosaria Conte, Raffaele De Palma, Lucia Altucci
In recent years, anti-tumor immunotherapy has shown promising results, and immune-oncology is now emerging as the fourth major wave in the treatment of tumors after radiotherapy, chemotherapy and molecular targeted therapy. Understanding the impact of the immune system on neoplastic cells is crucial to improve its effectiveness against cancer. The stratification of patients who might benefit from immunotherapy as well as the personalization of medicine have contributed to the discovery of new immunotherapeutic targets and molecules...
March 10, 2018: International Journal of Biochemistry & Cell Biology
Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Maria Dolores Sanchez-Niño, Lara Valiño-Rivas, Marta Ruiz-Ortega, Alberto Ortiz, Ana Belén Sanz
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease...
March 9, 2018: Nephrology, Dialysis, Transplantation
Chunlong Zhao, Jie Zang, Qin'ge Ding, Elizabeth S Inks, Wenfang Xu, C James Chou, Yingjie Zhang
In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (∼30-fold) which was confirmed by western blot analysis...
March 6, 2018: European Journal of Medicinal Chemistry
Kyle T Householder, Danielle M DiPerna, Eugene P Chung, Anne Rosa Luning, Duong T Nguyen, Sarah E Stabenfeldt, Shwetal Mehta, Rachael W Sirianni
Histone deacetylases (HDACs) are known to be key enzymes in cancer development and progression through their modulation of chromatin structure and the expression and post-translational modification of numerous proteins. Aggressive dedifferentiated tumors, like glioblastoma, frequently overexpress HDACs, while HDAC inhibition can lead to cell cycle arrest, promote cellular differentiation and induce apoptosis. Although multiple HDAC inhibitors, such as quisinostat, are of interest in oncology due to their potent in vitro efficacy, their failure in the clinic as monotherapies against solid tumors has been attributed to poor delivery...
February 24, 2018: Colloids and Surfaces. B, Biointerfaces
Stephen Shinsky, David W Christianson
Polyamines such as putrescine, spermidine, and spermine are small aliphatic cations that serve myriad biological functions in all forms of life. While polyamine biosynthesis and cellular trafficking pathways are generally well defined, it is only recently that the molecular basis of reversible polyamine acetylation has been established. In particular, enzymes that catalyze polyamine deacetylation reactions have been identified and structurally characterized: histone deacetylase 10 (HDAC10) from Homo sapiens and Danio rerio (zebrafish) is a highly specific N8-acetylspermidine deacetylase, and its prokaryotic counterpart, acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa, is a broad-specificity polyamine deacetylase...
March 13, 2018: Biochemistry
Zlatka Georgieva Dobreva, Boncho Grigorov Grigorov, Spaska Angelova Stanilova
BACKGROUND: Interleukin-18 (IL-18) and Tumor Necrosis Factor-alpha (TNF-α) are proinflammatory cytokines that increased the development of Th1 immune response, but have a different type of regulation of the gene expression. Whereas TNF-α has an inducible expression, IL-18 is translated as an inactive protein and required proteolytic cleavage by Casp-1 in inflammasome complexes. AIM: To investigate the effect of the histone deacetylases inhibitor Suberoylanilide Hydroxamic Acid (SAHA) on the gene expression and secretion of both cytokines, IL-18 and TNF-α, according to their contribution to the cancer development and anticancer immunity...
February 15, 2018: Open Access Macedonian Journal of Medical Sciences
Luye Qin, Kaijie Ma, Zi-Jun Wang, Zihua Hu, Emmanuel Matas, Jing Wei, Zhen Yan
Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits...
March 12, 2018: Nature Neuroscience
Di Yang, ChenXi Xiao, Fen Long, ZhengHua Su, WanWan Jia, Ming Qin, MengWei Huang, WeiJun Wu, Rinkiko Suguro, XinHua Liu, YiZhun Zhu
Aims: Angiotensin II (Ang II) causes vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of cardiovascular diseases. Therefore, interventions in inflammation may contribute to the reduction of cardiovascular diseases. Here, we aim to demonstrate that HDAC4, one of class IIa family histone deacetylases (HDACs) members, promotes autophagy-dependent vascular inflammation. Methods and results: By loss-of-function approaches, our study provides the first evidence that HDAC4 mediates Ang II-induced vascular inflammation in vitro and in vivo...
February 24, 2018: Cardiovascular Research
Michelle L Ratay, Stephen C Balmert, Ethan J Bassin, Steven R Little
Dry eye disease (DED), also known as keratoconjunctivitis sicca, is an ocular surface disease characterized by T-cell-mediated inflammation. Current therapeutics, such as immunosuppressive agents, act to suppress the clinical signs and inflammation. However, long-term usage of these treatments can cause severe side effects. In this study, we present an alternative therapeutic approach that utilizes a histone deacetylase inhibitor (HDACi) to regulate transcription of a variety of immunomodulatory genes. Specifically, HDACi have emerged as a potential anti-inflammatory agent, which can modulate the functions of a subset of suppressive T lymphocytes known as regulatory T cells (Tregs), enhancing FoxP3 acetylation and subsequently guarding the transcription factor from proteasomal degradation...
March 8, 2018: Acta Biomaterialia
Christina Li-Ping Thio, Po-Yu Chi, Alan Chuan-Ying Lai, Ya-Jen Chang
BACKGROUND: Allergic asthma is characterized airway hyperreactivity (AHR) and inflammation driven by aberrant TH 2 response. Type 2 innate lymphoid cells (ILC2s) are a critical source of TH 2 cytokines IL-5 and IL-13 which promote acute asthma exacerbation. Short chain fatty acids (SCFAs) have been shown to attenuate T cell-mediated allergic airway inflammation. Their role in the regulation of ILC2-driven AHR and lung inflammation, however, remains unknown. OBJECTIVE: We investigated the immunomodulatory role of SCFAs in the regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved...
March 6, 2018: Journal of Allergy and Clinical Immunology
John Peyton Bohnsack, Benjamin A Hughes, Todd K O'Buckley, Kamyra Edokpolor, Joyce Besheer, A Leslie Morrow
Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAA R) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAA R hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chronic ethanol exposure is still unknown. We found that chronic ethanol exposure using either ethanol gavage or two-bottle choice voluntary access paradigms decreased Gabra1 expression and increased Hdac2 and Hdac3 expression...
February 27, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Lore Becker, Melanie Schmitt Nogueira, Caroline Klima, Martin Hrabe de Angelis, Shahaf Peleg
Epigenetic deregulation, such as the reduction of histone acetylation levels, is thought to be causally linked to various maladies associated with aging. Consequently, histone deacetylase inhibitors are suggested to serve as epigenetic therapy by increasing histone acetylation. However, previous work suggests that many non-histone proteins, including metabolic enzymes, are also acetylated and that post transitional modifications may impact their activity. Furthermore, deacetylase inhibitors were recently shown to impact the acetylation of a variety of proteins...
March 8, 2018: Scientific Reports
Mitsuaki Yamashita, Teruyuki Tahara, Shinya Hayakawa, Hironobu Matsumoto, Shun-Ichi Wada, Kiyoshi Tomioka, Akira Iida
HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated...
February 27, 2018: Bioorganic & Medicinal Chemistry
Jia Liu, Wenting Lu, Shuang Liu, Ying Wang, Saisai Li, Yingxi Xu, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Min Wang, Jianxiang Wang
The t(8;21)(q22;q22) translocation generated the fusion protein AML1-ETO. AML1-ETO recruits histone deacetylase (HDAC) complex via its ETO part to repress AML1-mediated transactivation. Our previous study demonstrated that HDAC inhibitor phenylbutyrate (PB) could induce AML1-ETO positive leukemia cell line Kasumi-1 cells to undergo differentiation and apoptosis accompanied by significant changes in gene expression profile. ZFP36L2 was one of the up-regulated genes in Kasumi-1 cells induced by PB treatment. In this study, ZFP36L2 was found to express at a lower level in acute myeloid leukemia (AML) patients with t(8;21) compared to AML patients without t(8;21)...
February 27, 2018: Leukemia Research
Huong Mai Nguyen, Kaori Sako, Akihiro Matsui, Minoru Ueda, Maho Tanaka, Akihiro Ito, Norikazu Nishino, Minoru Yoshida, Motoaki Seki
Histone acetylation plays a pivotal role in plant growth and development, and is regulated by the antagonistic relationship between histone acetyltransferase (HAT) and histone deacetylase (HDAC). We previously revealed that some HDAC inhibitors confer high-salinity stress tolerance in plants. In this study, we identified two HDAC inhibitors, namely Ky-9 and Ky-72, which enhanced the high-salinity stress tolerance of Arabidopsis thaliana. Ky-9 and Ky-72 are structurally similar chlamydocin analogs. However, the in vitro inhibitory activity of Ky-9 against mammalian HDAC is greater than that of Ky-72...
March 8, 2018: Plant Signaling & Behavior
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