Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma

Fournier, Jean-François; Bhurruth-Alcor, Yushma; Musicki, Branislav; Aubert, Jacques; Aurelly, Michèle; Bouix‐Peter, Claire; Bouquet, Karinne; Chantalat, L.; Delorme, M.; Drean, Bénédicte; Duvert, G.; Fleury‐Brégeot, Nicolas; Gauthier, B; Grisendi, Karine; Harris, Craig S.; Hennequin, Laurent; Isabet, T.; Joly, Florence; Lafitte, Guillaume; Millois, Corinne; Morgentin, Rémy; Pascau, Jonathan; Piwnica, David; Rival, Yves; Soulet, Catherine; Thoreau, E.; Tomas, Loïc

doi:10.1016/j.bmcl.2018.06.029

Cited by 18 publications

(16 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…21,22 HDACs are overexpressed in different tumors types, and HDAC expression levels are closely related to prognosis. [23][24][25] Inhibition of HDACs can induce cell growth arrest and apoptosis in a variety of malignant cells, including breast cancer cells, 26 prostate cancer cells, 27 HCC cells, 28 pancreatic cancer cells, 29 lymphoma cells, 30 and lung cancer cells. 31 Thus, HDACs are considered therapeutic targets for various tumors.…”

Section: Introductionmentioning

confidence: 99%

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

Wang

Qiang

et al. 2020

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is a common malignant tumor. LukS-PV is the S component of Panton-Valetine leukocidin (PVL), which is secreted by Staphylococcus aureus. This study investigated the effects of LukS-PV on the proliferation, apoptosis, and cell-cycle progression of HCC cells and the mechanisms of its activity. The HCC cells were treated with different LukS-PV concentrations in vitro. Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to study cell proliferation. Flow cytometry was used to measure apoptosis and cell-cycle progression. Quantitative reverse transcriptase PCR and western blot assays were used to determine mRNA and protein expression levels. Xenograft experiments were performed to determine the in vivo antitumor effect of LukS-PV. Immunostaining was performed to analyze Ki-67 and HDAC2 (histone deacetylase 2) expression. Our results showed that LukS-PV inhibited cell proliferation and induced apoptosis in a concentration-dependent manner in HCC cell lines. LukS-PV also can induce cell-cycle arrest. Moreover, we discovered that LukS-PV attenuated HDAC2 expression and upregulated PTEN; phosphorylated AKT was also reduced. Further studies demonstrated that LukS-PV treatment significantly reduced tumor growth in nude mice and suppressed Ki-67 and HDAC2 levels. Our data revealed a vital role of LukS-PV in suppressing HCC progression by downregulating HDAC2 and upregulating PTEN.

show abstract

Section: Introductionmentioning

confidence: 99%

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

Wang

Qiang

et al. 2020

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

show abstract

“…Furthermore, the zinc ion is accompanied by Asp181, His183, and Asp269 (62)(63)(64). HdAc2 inhibitors typically have a pharmacophore comprising three sectors: A zinc-binding group, a linker portion and a hydrophobic cap group (65)(66)(67). Based on molecular docking and virtual screening techniques, a series of compounds with novel skeletal structures have been identified as HdAc inhibitors, and their inhibitory activities and clinical therapeutic effects have been investigated (68,69).…”

Section: Hdac2mentioning

confidence: 99%

“…Venturelli et al ( 133 ) reported that 6- and 8-prenylnaringenin enter into the 'foot pocket' of HDAC2 and combine with zinc ion of their catalytic center, subsequently inhibiting excessive proliferation of melanoma cells. N-[4-(Hydrazinecarbonyl)phenyl]-3,5,6-trimethylpyr- azine-2-carboxamide exhibits notable anticancer activity in vivo (IC 50 =1.60 μ M) ( 134 ) Among squaramide-based derivatives, the lead compound 42 exhibits good druggability by specifically inhibiting HDAC2 ( 67 ). Isopropyl derivative 5 and tert-butyl derivative 6, is which derived from the lead compound NSC746457, exhibit a significantly inhibitory effect on HDAC2 ( 63 ).…”

Section: Hdac2 In Liver Diseasementioning

confidence: 99%

Histone deacetylase‑2: A potential regulator and therapeutic target in liver disease (Review)

et al. 2021

View full text Add to dashboard Cite

Histone acetyltransferases are responsible for histone acetylation, while histone deacetylases (HdAcs) counteract histone acetylation. An unbalanced dynamic between histone acetylation and deacetylation may lead to aberrant chromatin landscape and chromosomal function. HdAc2, a member of class I HdAc family, serves a crucial role in the modulation of cell signaling, immune response and gene expression. HdAc2 has emerged as a promising therapeutic target for liver disease by regulating gene transcription, chromatin remodeling, signal transduction and nuclear reprogramming, thus receiving attention from researchers and clinicians. The present review introduces biological information of HdAc2 and its physiological and biochemical functions. Secondly, the functional roles of HdAc2 in liver disease are discussed in terms of hepatocyte apoptosis and proliferation, liver regeneration, hepatocellular carcinoma, liver fibrosis and non-alcoholic steatohepatitis. Moreover, abnormal expression of HdAc2 may be involved in the pathogenesis of liver disease, and its expression levels and pharmacological activity may represent potential biomarkers of liver disease. Finally, research on selective HdAc2 inhibitors and non-coding RNAs relevant to HdAc2 expression in liver disease is also reviewed. The aim of the present review was to improve understanding of the multifunctional role and potential regulatory mechanism of HdAc2 in liver disease.

show abstract

“…As far as HDACs are concerned, several 3D structures of different human isoforms are available in the Protein Data Bank. Examples are given by several X-ray structures, in complex with inhibitors, of HDAC2 (PDB codes 3MAX, 5IX0, 5IWG, 6WBZ, 6WBW, 6G3O, 4LXZ, and 4LY1 ), HDAC4 (PDB codes 2VQQ, 2VQM, 2VQJ, 5A2S, 4CBY, 4CBT, and 6FYZ ), HDAC7 (PDB codes 3ZNR, 3ZNS, 3C0Z, and 3C10 ), and HDAC8 (PDB codes 1VKG, 1T64, 5D1B, 1T69, 1T67, and 2V5X ). Some of these structures have been successfully employed in the past years to identify, for instance, HDAC4, HDAC8, dual MMP-2/HDAC-8, and dual MMP2/HDAC-6 inhibitors by means of SBRD strategies.…”

Section: In Silico Approaches For the Identification Of Dual Cb2r/hda...mentioning

confidence: 99%

Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration

et al. 2020

View full text Add to dashboard Cite

The cannabinoid receptor subtype 2 (CB2R) represents an interesting and new therapeutic target for its involvement in the first steps of neurodegeneration as well as in cancer onset and progression. Several studies, focused on different types of tumors, report a promising anticancer activity induced by CB2R agonists due to their ability to reduce inflammation and cell proliferation. Moreover, in neuroinflammation, the stimulation of CB2R, overexpressed in microglial cells, exerts beneficial effects in neurodegenerative disorders. With the aim to overcome current treatment limitations, new drugs can be developed by specifically modulating, together with CB2R, other targets involved in such multifactorial disorders. Building on successful case studies of already developed multitarget strategies involving CB2R, in this Perspective we aim at prompting the scientific community to consider new promising target associations involving HDACs (histone deacetylases) and σ receptors by employing modern approaches based on molecular hybridization, computational polypharmacology, and machine learning algorithms.

show abstract

Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma

Cited by 18 publications

References 21 publications

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

Histone deacetylase‑2: A potential regulator and therapeutic target in liver disease (Review)

Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration

Contact Info

Product

Resources

About