Epi-revolution in rheumatology: the potential of histone deacetylase inhibitors for targeted rheumatoid arthritis intervention.

Autoimmune diseases hold significant importance in the realm of medical research, prompting a thorough exploration of potential therapeutic interventions. One crucial aspect of this exploration involves understanding the intricate processes of histone acetylation and deacetylation. Histone acetylation, facilitated by histone acetyl transferases (HATs), is instrumental in rendering DNA transcriptionally active. Conversely, histone deacetylases (HDACs) are responsible for the removal of acetyl groups, influencing gene expression regulation. The upregulation of HDACs, observed in various cancers, has steered attention towards histone deacetylase inhibitors (HDACi) as promising anti-cancer agents. Beyond cancer, HDACi has demonstrated anti-inflammatory properties, prompting interest in their potential therapeutic applications for inflammatory diseases such as rheumatoid arthritis (RA). RA, characterized by the immune system erroneously attacking healthy cells, leads to joint inflammation. Recent studies suggest that HDACi could offer a viable therapeutic strategy for RA, with potential mechanisms including the inhibition of synovial tissue growth and suppression of pro-inflammatory cytokines. Furthermore, HDACi may exert protective effects on bone and cartilage, common targets in RA pathology. In-depth investigations through in vivo and histopathology studies contribute to the ongoing discourse on the therapeutic benefits of HDACis in the context of RA treatment.

Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities.

BACKGROUND: Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy. OBJECTIVES: The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor. METHODS: The N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2. RESULTS: The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC50 of 16.43 µM. It displayed potent inhibitory activity against HDAC and RR with IC50 values of 10.80 µM and 9.34 µM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7. CONCLUSION: The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.

Synergistic therapeutics: Co-targeting histone deacetylases and ribonucleotide reductase for enhanced cancer treatment.

The development of cancer is influenced by several variables, including altered protein expression, and signaling pathways. Cancers are inherently heterogeneous and exhibit genetic and epigenetic aberrations; therefore, developing therapies that act on numerous biological targets is encouraged. To achieve this, two approaches are employed: combination therapy and dual/multiple targeting chemotherapeutics. Two enzymes, histone deacetylases (HDACs) and ribonucleotide reductase (RR), are crucial for several biological functions, including replication and repair of DNA, division of cells, transcription of genes, etc. However, it has been noted that different cancers exhibit abnormal functions of these enzymes. Potent inhibitors for each of these proteins have been extensively researched. Many medications based on these inhibitors have been successfully food and drug administration (FDA) approved, and the majority are undergoing various stages of clinical testing. This review discusses various studies of HDAC and RR inhibitors in combination therapy and dual-targeting chemotherapeutics.

Molecular Mutations in Histiocytosis: A Comprehensive Survey of Genetic Alterations.

Histiocytosis represents a group of uncommon disorders characterized by the abnormal accumulation of specialized immune cells, such as macrophages, dendritic cells, or monocyte-derived cells, in various tissues and organs. Over 100 distinct subtypes have been documented, each displaying a broad spectrum of clinical presentations and histological characteristics. Till today, histiocytosis has been addressed through a combination of chemotherapy, radiotherapy, and surgery, with varying responses from individual patients. Due to its atypical symptoms, it has been prone to misdiagnosis. Advances in our understanding of the cellular and molecular aspects of these conditions are paving the way for improved diagnostic methods and targeted therapies. Researchers have extensively investigated various mutations in patient samples. However, no paper has yet provided a comprehensive summary of the collective analysis of mutations and pathways. Hence, this paper consolidates research efforts that specifically concentrate on gene mutations identified in patient samples of different subtypes of histiocytosis. These insights are essential for developing targeted therapies and improving diagnosis. Further, it provides potential insights to enhance the development of more effective therapeutic approaches for rare diseases.

The role of histone deacetylases in embryonic development.

The basic units of chromatin are nucleosomes, that are made up of DNA wrapped around histone cores. Histone lysine residue is a common location for posttranslational modifications, with acetylation being the second most prevalent. Histone acetyltransferases (HATs/KATs) and histone deacetylases (HDACs/KDACs) regulate histone acetylation, which is important in gene expression control. HDACs/KDACs regulate gene expressions through the repression of the transcription machinery. HDAC/KDAC isoforms play a major role during various stages of embryo development and neurogenesis. In specific, class I and II HDACs/KDACs are involved in cardiac muscle differentiation and development. An insight into different pathways and genes associated with embryonic development, the effect of HDAC/KDAC activity during the embryonic stem cell differentiation, preimplantation, embryo development, gastrulation, and the role of different HDAC/KDAC inhibitors during the process of embryogenesis is summarized in the present review article.

Identification of potent HDAC 2 inhibitors using E-pharmacophore modelling, structure-based virtual screening and molecular dynamic simulation.

Histone deacetylase 2 (HDAC 2) of class I HDACs plays a major role in embryonic and neural developments. However, HDAC 2 overexpression triggers cell proliferation by diverse mechanisms in cancer. Over the decades, many pan and class-specific inhibitors of HDAC were discovered. Limitations such as toxicity and differential cell localization of each isoform led researchers to hypothesize that isoform selective inhibitors may be relevant to bring about desired effects. In this study, we have employed the PHASE module to develop an e-pharmacophore model and virtually screened four focused libraries of around 300,000 compounds to identify isoform selective HDAC 2 inhibitors. The compounds with phase fitness score greater than or equal to 2.4 were subjected to structure-based virtual screening with HDAC 2. Ten molecules with docking score greater than -12 kcal/mol were chosen for selectivity study, QikProp module (ADME prediction) and dG/bind energy identification. Compound 1A with the best dock score of -13.3 kcal/mol and compound 1I with highest free binding energy, -70.93 kcal/mol, were selected for molecular dynamic simulation studies (40 ns simulation). The results indicated that compound 1I may be a potent and selective HDAC 2 inhibitor. Further, in vitro and in vivo studies are necessary to validate the potency of selected lead molecule and its derivatives.

Histone deacetylase 2 selective inhibitors: A versatile therapeutic strategy as next generation drug target in cancer therapy.

Acetylation and deacetylation of histone and several non-histone proteins are the two important processes amongst the different modes of epigenetic modulation that are involved in regulating cancer initiation and development. Abnormal expression of histone deacetylases (HDACs) is often reported in various types of cancers. Few pan HDAC inhibitors have been approved for use as therapeutic interventions for cancer treatment including vorinostat, belinostat and panobinostat. However, not all the HDAC isoforms are abnormally expressed in certain cancers, such as in the case of, ovarian cancer where overexpression of HDAC1-3, lung cancer where overexpression of HDAC 1 and 3 and gastric cancer where overexpression of HDAC2 is seen. Therefore, pan-inhibition of HDAC is not an efficient way to combat cancer via HDAC inhibition. Hence, isoform-selective HDAC inhibition can be one of the best therapeutic strategies in the treatment of cancer. In this context since aberrant expression of HDAC2 largely contributes to cancer progression by silencing pro-apoptotic protein expressions such as NOXA and APAF1 (caspase 9-activating proteins) and inactivation of tumor suppressor p53, HDAC2 specific inhibitors may help to develop not only the direct targets but also indirect targets that are crucial for tumor development. However, to develop a HDAC2 specific and potent inhibitor, extensive knowledge of its structure and specific functions is essential. The present review updates details on the structural features, physiological functions, and roles of HDAC2 in different types of cancer, emphasizing the challenges and status of the development of HDAC2 selective inhibitors against various types of cancer.