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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
This class comprises of HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10 (Figure 8.2B) (Seto and Yoshida, 2014). Class II proteins exhibit similarity in amino acids sequence to the yeast Hda1 protein (Yang and Gregoire, 2005). Class II enzymes are further subdivided into class IIa—consisting of HDAC4, 5, 7 and 9—and Class IIb, consisting of HDAC6 and 10 (Park and Kim, 2020). Class IIa enzymes shuttle between nucleus and cytoplasm, and form large complex structures by interacting with other proteins, while Class IIb HDACs are located mainly in the cytoplasm. HDAC6 is a well-characterized cytoplasmic deacetylase (Figure 8.1C). The catalytic domains of Class II HDACs contain a structural zinc ion-binding subdomain and exhibit at least 1,000-fold lower enzymatic activity when compared with that of class I HDACs (Park and Kim, 2020).
The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Heat shock proteins (HSP) are another potentially important set of targets of HDAC inhibitors. It has been shown that HSP90 serves as a chaperone protein required for proper folding and maintenance of numerous signaling protein kinases like Bcr-Abl, FLT3, AKT, and c-Raf in their active formations (31). HDAC6 is an enzyme responsible for deacetylation of HSP90, which keeps HSP90 active in its chaperone function. Inhibition of HDAC6 causes HSP90 acetylation and disruption of its chaperone function leading to polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client proteins, making such cells more susceptible to other antineoplastic agents (32).
A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Abbas Hassan, Abid Hussain Khan, Faiza Saleem, Haseen Ahmad, Khalid Mohammed Khan
Histone deacetylase 6 (HDAC6) is the best-characterized deacetylase regulating biological processes as it forms complexes with specific proteins. HDAC6 is substrate specific for non-histone proteins such as Hsp90, peroxiredoxins, cortactin, and α-tubulin. The unique function of HDAC6 suggests that it could work as a potential therapeutic target to treat a wide range of diseases. HDAC6 is deregulated in cancers, inflammatory diseases, and neurodegenerative disorders. Extensive efforts have led to the discovery of very few HDAC6-selective inhibitors. Hydroxamic acid pharmacophores are used as a zinc-binding group in most reported compounds [44]. These inhibitors are useful for the treatment of life-threatening diseases such as cancer, autoimmune diseases, inflammatory diseases, neurological diseases, and neurodegenerative disorders [45]. HDAC6 inhibitors should have a selective nature as non-selective inhibitors can cause many side effects [46].
Molecular design, synthesis and in vitro biological evaluation of thienopyrimidine–hydroxamic acids as chimeric kinase HDAC inhibitors: a challenging approach to combat cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Mona M. Abdel-Atty, Nahla A. Farag, Rabah A. T. Serya, Khaled A. M. Abouzid, Samar Mowafy
The development of multitarget drug therapy has become an important strategy for cancer treatment. Recently, the modulation of receptor tyrosine kinase (RTK) pathways by the inhibition of histone deacetylases (HDACs) has become a promising approach for cancer therapy1. HDACs are a family of numerous epigenetic enzymes that are important therapeutic targets for cancer2. HDACs have been classified into four distinct classes, in which class I (HDAC1–3 and 8), class II (HDAC4–7, 9 and 10), and class IV (HDAC11)3. HDAC6 is considered a therapeutically important target for cancer treatment due to its interaction with proteins involved in cell growth, migration, protein degradation, and apoptosis4. It is reported that HDAC inhibitors with large or rigid hydrophobic surface recognition moiety (SRM) and bulky aromatic or short linkers, are more efficient to achieve HDAC6 selectivity, which could achieve a closer approach of the hydroxamate group to Zn2+5. Numerous HDAC6 inhibitors have been developed having large SRM connected to the zinc-binding group (ZBG) with diverse linkers (Figure 1)5–7.
Inhibition of HDAC6 alleviating lipopolysaccharide-induced p38MAPK phosphorylation and neuroinflammation in mice
Published in Pharmaceutical Biology, 2019
Yuanjian Song, Li Qin, Rongli Yang, Fan Yang, Nwobodo Alexander Kenechukwu, Xiaofang Zhao, Xiaoyan Zhou, Xiangru Wen, Lei Li
Studies have shown that LPS induces the production of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which affects the brain function (Zhang et al. 2017). According to recent reports, peripherally injected LPS directly induces microglial activation and brain injury in rats. Therefore, intraperitoneal (I.P.) administered LPS can be used to prepare animal models of brain injury with inflammation. No reliable drugs are available for these neurodegenerative diseases (Fu et al. 2015). Though it has been reported that HDAC6 may emerge as a promising therapeutic target, genetic and pharmacological inhibition of HDAC6 have been shown to suppress neurodegenerative disorders, enhance immunomodulatory activity and alleviate disorder behaviors in animal models (Jianhua et al. 2017; Martin et al. 2017). Also, suppression of HDAC6 activity significantly restrains the LPS-induced production of pro-inflammatory cytokines (Yoo et al. 2016). The anti-inflammatory action of the HDAC6-selective inhibitor Tubastatin A (TBSA) has recently been shown to decrease inflammation of rat thermal injury (Shen et al. 2015). Thus, TBSA is an ideal drug for some inflammatory diseases in the brain. However, the molecular mechanisms of HDAC6 in brain diseases require further studies. In the present study, we examined the effect of HDAC6 on the phosphorylation of p38MAPK and the expression of TNF-α and IL-6 to investigate whether p38MAPK was involved in the HDAC6-relative neuroinflammation induced by LPS.