Design, synthesis, modeling, biological evaluation and photoaffinity labeling studies of novel series of photoreactive benzamide probes for histone deacetylase 2

Vaidya, Aditya S.; Karumudi, Bhargava; Mendonca, Emma; Madriaga, Antonett; Abdelkarim, Hazem; Breemen, Richard B. van; Petukhov, Pavel A.

doi:10.1016/j.bmcl.2012.06.017

Cited by 14 publications

(16 citation statements)

References 21 publications

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“…HDAC activity assays were performed in 96-well opaque microplates as previously described29. 20 μg of HeLa nuclear extract (Promega) or 50 ng recombinant Flag-HDAC 2 (BPS Bioscience) were diluted in assay buffer 1 (25 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 , and 1 mg/mL BSA) and incubated with the indicated amounts of pharmacological compounds, purified actin (Cytoskeleton Inc.) or BSA (Sigma-Aldrich) for 15 m at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A Role for Nuclear Actin in HDAC 1 and 2 Regulation

Serebryannyy

Cruz

Lanerolle

2016

Sci Rep

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Class I histone deacetylases (HDACs) are known to remove acetyl groups from histone tails. This liberates positive charges on the histone tail and allows for tighter winding of DNA, preventing transcription factor binding and gene activation. Although the functions of HDAC proteins are becoming apparent both biochemically and clinically, how this class of proteins is regulated remains poorly understood. We identified a novel interaction between nuclear actin and HDAC 1 and HDAC 2. Nuclear actin has been previously shown to interact with a growing list of nuclear proteins including chromatin remodeling complexes, transcription factors and RNA polymerases. We find that monomeric actin is able to bind the class I HDAC complex. Furthermore, increasing the concentration of actin in HeLa nuclear extracts was able to suppress overall HDAC function. Conversely, polymerizing nuclear actin increased HDAC activity and decreased histone acetylation. Moreover, the interaction between class I HDACs and nuclear actin was found to be activity dependent. Together, our data suggest nuclear actin is able to regulate HDAC 1 and 2 activity.

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Section: Methodsmentioning

confidence: 99%

A Role for Nuclear Actin in HDAC 1 and 2 Regulation

Serebryannyy

Cruz

Lanerolle

2016

Sci Rep

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“…[29, 39] . Stock solutions of human recombinant HDAC 1, 2 and 3 (BPS Bioscience) and HDAC8 (purified from E. coli) were prepared in assay buffer 1 (25 mM Tris–HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 , and 1 mg/mL BSA).…”

Section: Methodsmentioning

confidence: 99%

“…HDAC activity assay: Carried out as described in published detailed experimental procedures using recombinant HDAC1, 2, 3 and 8. [29,39] Stock solutions of human recombinant HDAC1, 2 and 3 (BPS Bioscience) and HDAC8 (purified from E. coli) were prepared in assay buffer 1 (25 mm Tris-HCl, pH 8.0, 137 mm NaCl, 2.7 mm KCl, 1 mm MgCl 2 , and 1 mg mL À1 BSA). Serial dilutions of the probes were made in assay buffer 2 (25 mm Tris-HCl, pH 8.0, 137 mm NaCl, 2.7 mm KCl, 1 mm MgCl 2 ).…”

Section: Synthetic Proceduresmentioning

confidence: 99%

A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy

et al. 2013

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Breast cancer remains a significant cause of death in women and few therapeutic options exist for estrogen receptor negative ER(−) cancers. Epigenetic re-activation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER(−) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER(+) cancer treatment. Based upon preliminary studies in ER(+) and ER(−) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs were designed with computational guidance. Assay for inhibition of four Type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a “SERMostat” with 1–3 μM potency across all targets. The superior hybrid caused significant cell death in ER(−) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.

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“…4 Due to their role in various biological functions, HDAC inhibition has become a promising epigenetic target for the treatment of cancer. 5 HDAC inhibitors (HDACis) are structurally diverse and are classified into various groups as hydroximates, [6][7][8] cyclic tetrapeptides, 9 benzamides, 10,11 electrophilic ketones, 12 and carboxylic acids. 13 Two HDACis (vorinostat and romidepsin) have been approved by the United States Food and Drug Administration for the treatment of cutaneous T-cell lymphoma.…”

Section: Introductionmentioning

confidence: 99%

Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study

Debnath¹,

Debnath²,

Majumdar³

et al. 2015

RRMC

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In recent years, histone deacetylases (HDACs) have been considered one of the promising targets for cancer chemotherapy. In the present study, a six-featured pharmacophore model with two hydrogen bond acceptors (AA), two hydrogen bond donors (DD), and two aromatic rings (RR) was developed. A predictive three-dimensional quantitative structure-activity relationship model was generated using the pharmacophore models obtained. The model has an excellent correlation coefficient and good predictive ability, as shown by the significant statistical parameters for both the training set (R 2 =0.9565, standard deviation =0.1171, F=99, and number of ligands in training set =21) and test set (Q 2 =0.8468, Pearson's R=0.9363, number of ligands in test set =9) molecules. The pharmacophore model was employed for the virtual screening of molecules with HDAC8 activity. The screening resulted in 366 hits with predicted activity as HDAC8 inhibitors. The hits obtained from the virtual screening were subjected to a molecular docking study to identify the potent inhibitors that binds to the active site with high affinity. The molecular docking study of known inhibitors and their analysis showed that the crucial interacting amino acid residues of HDAC8 are TYR-306, HIS-142, PHE-152, TYR-100, HIE-180, PHE-207, and Zn-388. On the basis of fitness score, predicted activities, XP Glide score, ADME results, and interacting amino acid residues, ten structurally diverse hits were reported in this paper as HDAC8 inhibitors.

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Design, synthesis, modeling, biological evaluation and photoaffinity labeling studies of novel series of photoreactive benzamide probes for histone deacetylase 2

Cited by 14 publications

References 21 publications

A Role for Nuclear Actin in HDAC 1 and 2 Regulation

A Role for Nuclear Actin in HDAC 1 and 2 Regulation

A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy

Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study

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Design, synthesis, modeling, biological evaluation and photoaffinity labeling studies of novel series of photoreactive benzamide probes for histone deacetylase 2

Cited by 14 publications

References 21 publications

A Role for Nuclear Actin in HDAC 1 and 2 Regulation

A Role for Nuclear Actin in HDAC 1 and 2 Regulation

A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy

Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure&ndash;activity relationship, and docking study

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Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study