Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors

Zhao, Cui; Zang, Jie; Ding, Qin'ge; Inks, Elizabeth S.; Xu, Wenjian; Chou, C. James; Zhang, Yingjie

doi:10.1016/j.ejmech.2018.03.002

Cited by 32 publications

(20 citation statements)

References 23 publications

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“…9). 94 Neelarapu et al described potent isoxazole-and pyrazolebased HDAC3 and HDAC8 diazide probes. 95 The bulky substituent in the para position of the terminal phenyl ring of target compounds leads to its lower activities for HDAC8 and compounds with the azide group exhibited tolerable HDAC8 inhibitory activities.…”

Section: Class I Selective Hdacismentioning

confidence: 99%

Next-generation of selective histone deacetylase inhibitors

et al. 2019

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Section: Class I Selective Hdacismentioning

confidence: 99%

Next-generation of selective histone deacetylase inhibitors

et al. 2019

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“…Recent research also revealed some unique structural features in this isoform, which distinguish it from other HDACs and which can be utilized to design selective inhibitors [60]. As a result, a variety of probes emerged (Figure 3) that showed preferential in vitro inhibition of HDAC8 compared to other isoforms ( [61][62][63][64][65][66], reviewed in [67,68]). Several studies suggest that combination therapies of epigenetic modulators could achieve better clinical results than a monotherapy, especially against solid and resistant tumors (reviewed in [69]).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Ghazy

Zeyen

Herp

et al. 2020

European Journal of Medicinal Chemistry

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Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.

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“…Unfortunately, these FDA approved drugs are relatively non-selective and inhibit most of the zincdependent HDAC subtypes (Yang, 2011;Qiao et al, 2013), which could cause several mild or severe toxic effects associated with the treatment, such as dehydration, thrombocytopenia, anorexia, and cardiac arrhythmia (Chakrabarti et al, 2016;Buonvicino et al, 2018;Cosenza and Pozzi, 2018;Laino et al, 2019). In addition, due to the physicochemical properties of hydroxamic acid group as the ZBG, some drawbacks have been exposed, including poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity, making the design and discovery of HDAC inhibitors with novel zinc binding group (ZBG) more necessary (Di Micco et al, 2008;Botta et al, 2011;Burli et al, 2013;Zhao et al, 2018;Banerjee et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

Wang

Liu

et al. 2020

Front. Chem.

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Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds a6, a9, a10, b8, and b9 exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds a9 and b8 on Hela's cytostatic activity (a9: IC 50 = 11.15 ± 3.24 µM; b8: IC 50 = 13.68 ± 1.31 µM). The enzyme inhibition assay against Hela extracts and HDAC1&6 subtypes showed that compound a9 had a certain broad-spectrum inhibitory activity, while compound b8 had selective inhibitory activity against HDAC6, which was consistent with Western blot results. In addition, the inhibitory mechanism of compounds a9 and b8 in HDAC1&6 were both compared through computational approaches, and the binding interactions between the compounds and the enzymes target were analyzed from the perspective of energy profile and conformation. In summary, the compounds with novel ZBG exhibited certain antitumor activities, providing valuable hints for the discovery of novel HDAC inhibitors.

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Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors

Cited by 32 publications

References 23 publications

Next-generation of selective histone deacetylase inhibitors

Next-generation of selective histone deacetylase inhibitors

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

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