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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
HDAC3’s phospho-acceptor site, S424, which is a non-conserved residue among the Class I HDACs, when mutated to alanine severely compromises enzymatic activity of HDAC1 and HDAC2. Unlike HDAC1 and HDAC2, the HDAC3 associates with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1), and dephosphorylation of HDAC3 by PP4 down-regulates HDAC3 enzymatic activity (Zhang et al., 2005). Phosphorylation of HDAC8 at S39 leads to the disruption in the surface structure, which ultimately leads to the negative effect of HDAC8. Phosphorylation of Class IIa HDACs may lead to their ubiquitination and proteasomal degradation. Two phosphatases have been implicated in the regulation of Class IIa HDACs activities and functions: protein phosphatase 1b (PP1b), including myosin phosphatase targeting subunit 1 (MYPT1, a regulatory subunit of PP1), and protein phosphatase 2A (PP2A). Class IIb HDACs, global proteomic profiling of phosphopeptides, revealed that HDAC6 is phosphorylated at S22 and T30 (Beausoleil et al., 2004).
Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
It has been suggested since the early 1990s that curcumin can slow the growth of tumors and arrest angiogenesis. In 2003, researchers discovered that curcumin can irreversibly inhibit aminopeptidase N (APN), an enzyme that promotes tumor invasiveness and angiogenesis. APN is a membrane-bound, zinc-dependent metalloproteinase that breaks down proteins at the cell surface, thus helping tumor cells invade the space of neighboring cells. Through a combination of surface plasmon resonance experiments and in vitro enzyme assays it was established that curcumin’s inhibition of APN is direct and irreversible. Although the exact mode of binding is not yet established, it has been postulated that the two α,β-unsaturated ketone moieties may covalently link to nucleophilic amino acids in APN’s active site. In other mechanism of action studies, curcumin has been shown to inhibit epigenetic (e.g., histone deacetylases HDAC1, HDAC3, and HDAC8), arachidonate 5-lipoxygenase, and cyclooxygenase enzymes, and also transcriptional co-activator proteins (e.g., p300 histone acetyltransferase).
Roberts Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Apart from ESCO2-related RBS, mutations in SMC1, SMC3, RAD21, NIPBL, HDAC8, and cohesin-associated PDS5/APRIN causing defective SCC (the process in which sister chromatids are paired during the cell cycle) are implicated in the development of Cornelia de Lange syndrome (CdLS). In contrast to RBS, CdLS is a transcription-based disorder that does not exhibit elevated levels of apoptosis or mitotic failure, and its chromatin-bound cohesin is not only involved in sister chromatid tethering, but also transcription regulation (Figure 47.1) [14].
Discovery of novel polysubstituted N-alkyl acridone analogues as histone deacetylase isoform-selective inhibitors for cancer therapy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Ze Wang, Li Zhao, Bo Zhang, Jiahe Feng, Yule Wang, Bin Zhang, Haixiao Jin, Lijian Ding, Ning Wang, Shan He
To further evaluate the selective inhibitory activity against other HDAC isoforms (HDAC3, 8, 10), 11b and 11c were selected for activity screening, chidamide and SAHA were used as positive controls. As can be seen from Table 6, 11b and 11c with selective inhibitory activity of HDAC1, also exhibited significant inhibitory activity against HDAC3 (class I HDAC), with IC50 values of 418 nM and 225 nM, respectively. Moreover, similar to chidamide, these compounds showed strong inhibitory activity against HDAC10 (class II HDAC) with IC50 values of 387 nM and 177 nM, respectively. However, these two compounds showed no inhibitory activity against HDAC8 (class I HDAC). Among them, the inhibitory activity of 11c against HDAC3 and HDAC10 was more potent than that of chidamide. Therefore, 11b and 11c were selected as hit compounds in this study for subsequent anticancer mechanism studies.
Virtual screening and zebrafish models in tandem, for drug discovery and development
Published in Expert Opinion on Drug Discovery, 2023
David Hernández-Silva, Francisca Alcaraz-Pérez, Horacio Pérez-Sánchez, Maria Luisa Cayuela
There are different drugs on the market that have been discovered with VS techniques, including saquinavir, ritonavir, and indinavir (antiretroviral agents), saquinavir, ritonavir, and indinavir (three drugs for the treatment of human immunodeficiency virus) and others, which are in clinical phase III, such as nolatrexed, for the treatment of liver cancer [26,58–60]. As previously mentioned, there are also different studies in which the combination of both VS techniques (SBVS and LBVS) is applied, where different drugs were found that are much more potent than that which currently exists, such as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) [61,62]. It is worth mentioning that the use of these techniques for the development, improvement, and repositioning of drugs is, in general terms, a much faster and less expensive way than using a traditional experimental method. A key example is the discovery of specific inhibitors of histone deacetylase 8 (HDAC8).
Romidepsin (FK228) fails in counteracting the transformed phenotype of rhabdomyosarcoma cells but efficiently radiosensitizes, in vitro and in vivo, the alveolar phenotype subtype
Published in International Journal of Radiation Biology, 2021
Alessandra Rossetti, Francesco Petragnano, Luisa Milazzo, Francesca Vulcano, Giampiero Macioce, Silvia Codenotti, Matteo Cassandri, Silvia Pomella, Francesca Cicchetti, Irene Fasciani, Cristina Antinozzi, Luigi Di Luigi, Claudio Festuccia, Francesca De Felice, Massimo Vergine, Alessandro Fanzani, Rossella Rota, Roberto Maggio, Antonella Polimeni, Vincenzo Tombolini, Giovanni Luca Gravina, Francesco Marampon
Deregulation of class I HDACs, which includes HDAC1, HDAC2, HDAC3 and HDAC8, has been related to the onset and progression of several tumor types (Zhang et al. 2020), including RMS (Gryder et al. 2019). However, entinostat, a HDACi targeting the class I (Xu et al. 2007) and IV (Buglio et al. 2011), has provided a modest antitumor activity both in ARMS and ERMS pre-clinical models, alone or in combination with other cytotoxic agents usually used in RMS clinical setting (Bharathy et al. 2019; Kurmasheva et al. 2019). The reasons for this inefficiency are largely unknown and could be related to the poor selectivity of this drug. In fact, if the oncogenic potential of HDACs class I is now established, class IV has been shown to have also an antitumor potential (Leslie et al. 2019) and its inhibition could be responsible for the restrained therapeutic efficacy of the drug.