Antibodies
Belinostat (PXD101)
- 貨號 Cat. No.
- S1085
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
Belinostat (PXD101)
Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM, with activity demonstrated in cisplatin-resistant tumors. Phase 1/2.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM, with activity demonstrated in cisplatin-resistant tumors. Phase 1/2. | |||||
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| Targets | HDAC | |||||
| IC50 | 27 nM [1] | |||||
| In vitro | Belinostat inhibits the growth of tumor cells (A2780, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852) with IC50 from 0.2-0.66 μM. PD101 shows low activity in A2780/cp70 and 2780AD cells, which are cisplatin and doxorubicin-resistant derivatives of A2780 cells. Belinostat could induce apoptosis through PARP cleavage and acetylation of histones H3/H4. [1] Belinostat inhibits bladder cancer cell growth, especially in 5637 cells, which shows accumulation of G0-G1 phase, decrease in S phase and increase in G2-M phase. [2] The growth inhibitory activity of belinostat on cell lines is not strongly influenced by the multidrug-resistant phenotype, whereas the activity of docetaxel is clearly affected. Belinostat could enhance the growth inhibitory activity of docetaxel or carboplatin in OVCAR-3 and A2780 cells. Belinostat also shows enhanced tubulin acetylation in ovarian cancer cell lines. [3] A recent study shows that Belinostat activates protein kinase A in a TGF-β signaling-dependent mechanism and decreases survivin mRNA. [4] | |||||
| In vivo | Belinostat indicates significant tumor growth delay in A2780 and A2780/cp70 xenograft at a dose of 10mg/kg with no effects on the body weight. [1] Belinostat also induces p21WAF1, HDAC core and cell communication genes in mouse bladder tumors. [2] Belinostat monotherapy induces dose-proportional antitumor effects with TGI of 47% at a dose of 100mg/kg in A2780 xenograft. The combination of Belinostat (100 mg/kg) with carboplatin (40 mg/kg) could delay tumor growth from 18.6 days to 22.5 days. [3] Combining with bortezomib, Belinostat results in great tumor inhibition and gastrointestinal toxicity in mice with bortezomib-resistant UMSCC-11A xenograft. [5] | |||||
| Features | Lead compound of Topotarget. | |||||
Protocol(Only for Reference)
Kinase Assay: [1]
| Histone Deacetylase Activity | Subconfluent cultures are harvested and washed twice in ice cold PBS and pelleted by centrifugation at 200 × g for 5 min. The cell pellet is resuspended in two volumes of lysis buffer [60 mM Tris buffer (pH 7.4) containing 30% glycerol and 450 mM NaCl] and lysed by three freeze (dry ice) thaw (30 °C water bath) cycles. Cell debris is removed by centrifugation at 1.2 × 104 g for 5 min, and the supernatant is stored at −80 °C. Histone H4 peptide (sequence SGRGKGGKGLGKGGAKRHRK corresponding to the 20 NH2-terminal residues) is acetylated by a recombinant protein containing the hypoxanthine-aminopterin-thymidine domain of p300, using [3H]acetyl CoA as a source of acetate. H4 peptide (100 μg) is mixed with hypoxanthine-aminopterin-thymidine buffer (50 mM Tris HCl pH 8.0, 5% glycerol, 50 mM KCl, and 0.1 mM EDTA), 1 mM DTT, 1 mM 4-(2-aminoethyl) benzenesulfonylfluoride, 1 × complete protease inhibitors, 50 μL of purified p300, and 1.85 m [3H]acetyl CoA (4.50Ci/mmol) in a final volume of 300 μL and incubated at 30 °C for 45 min. The p300 protein is removed by incubation with 20 μL of 50% Ni-agaroase beads for 1 hour at 4 °C and centrifugation. The supernatant is applied to a 2 mL Sephadex G15 column, and the flow through is collected. One milliliter of distilled H2O is gently applied, and three drop fractions are collected; this is repeated until 4–5 mL of distilled H2O has been added, and ∼40 fractions are collected. Three microliters of each fraction are diluted in 2 mL of scintillation fluid and counted in a scintillation counter to identify the fractions containing the labeled peptide. These fractions are pooled, and 1 μL of the combined sample is measured to assess the radioactivity in every peptide batch (3-7×103 cpm/μL). For activity assays, the reaction is carried out in a total volume of 150 μL of buffer [60 mM Tris (pH 7.4) containing 30% glycerol] containing 2 μL of cell extract and, where used, 2 μL of belinostat. The reaction is started by the addition of 2 μL of [3H] labeled substrate (acetylated histone H4 peptide corresponding to the 20 NH2-terminal residues). Samples are incubated at 37 °C for 45 min, and the reaction stopped by the addition of HCl and acetic acid (0.72 and 0.12 M final concentrations, respectively). Released [3H]acetate is extracted into 750 μL of ethyl acetate, and samples are centrifuged at 1.2× 104 g for 5 min. The upper phase (600 μL) is transferred to 3 mL of scintillation fluid and counted. |
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Cell Assay: [1]
| Cell lines | A2780, A2780/cp70, 2780AD, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852 |
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| Concentrations | 0.016 - 10 μM |
| Incubation Time | 24 hours |
| Method | Tumor cell lines are seeded in 5 mL of medium at a density of 8 × 104 cells/25 cm2 flask and incubated for 48 hours. Cells are exposed to Belinostat (0.016 to 10 μM) for 24 hours. The medium is removed, and 1 mL of trypsin/EDTA is added to each flask. Once the cells have detached, 1 mL of medium is added, the cells are resuspended, and those from the control untreated flask are counted. Cells are diluted and plated into 6-cm Petri dishes (three per flask) at a density of 0.5-2× 103 cells/dish depending on the cell line. Cells from the drug-treated flasks are diluted and plated as for the control flasks. Dishes are incubated for 10–15 days at 37 °C. Cells are washed with PBS, fixed in methanol, and stained with crystal violet, and colonies that contained ≥50 cells counted. Sensitivity is expressed as the IC50 defined as the concentration of belinostat required to reduce the number of colonies to 50% of that of the control untreated cells. |
Animal Study: [1]
| Animal Models | A2780, A2780/cp70 and HCT116 cells are injected s.c. into the right flank of CD1 nu/nu mice. |
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| Dosages | ≤40 mg/kg |
| Administration | Administered via i.p. |
| Solubility | 1% DMSO/30% polyethylene glycol/1% Tween 80, 12 mg/mL |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01090830 | Terminated | Non-Small-Cell Lung Carcinoma | Holy Cross Hospital, Florida | 2010-04 | Phase 1|Phase 2 |
| NCT01310244 | Recruiting | Stage IV Non-small Cell Lung Cancer | Spectrum Pharmaceuticals, Inc|TopoTarget A/S | 2010-12 | Phase 1|Phase 2 |
| NCT01686165 | Recruiting | Anaplastic Large Cell Lymphoma|Recurrent Adult Diffuse Large Cell Lymphoma|Recurrent Mantle Cell Lymphoma | University of Arizona|Thomas P. Miller|National Cancer Institute (NCI) | 2012-09 | Phase 2 |
| NCT01839097 | Recruiting | Peripheral T-cell Lymphoma | Spectrum Pharmaceuticals, Inc | 2013-05 | Phase 1 |
| NCT01583777 | Not yet recruiting | Advanced Cancer | Spectrum Pharmaceuticals, Inc | 2013-07 | Phase 1 |
Chemical Information
Download Belinostat (PXD101) SDF
| Molecular Weight (MW) | 318.35 |
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| Formula | C15H14N2O4S |
| CAS No. | 414864-00-9 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 64 mg/mL (201 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | <1 mg/mL (<1 mM) | ||
| In vivo | 1% DMSO/30% polyethylene glycol/1% Tween 80, | 12 mg/mL | |
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | 2-Propenamide, N-hydroxy-3-[3-[(phenylamino)sulfonyl]phenyl]- |
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Preparing Stock Solutions
| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
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| Mass(mg) | 0.31835 | 3.1835 | 6.367 | 9.5505 |
Customer Reviews (5)
 Click to enlarge | Rating | |
| Source | Breast Cancer Res Treat 2010 131(3), 777-789. Belinostat (PXD101) purchased from Selleck | |
| Method | Western blot | |
| Cell Lines | MDA-MB-231 cells, MDA-MB-468 cells | |
| Concentrations | 0.5-10 μM | |
| Incubation Time | 24 h | |
| Results | In both MDA-MB-231 and MDA-MB-468 cell lines, exposure to these compounds produced significant global increase of nuclear H3K4me2,which is the specific substrate of LSD1.The enhanced level of histone methylation by PXD101 and other HDAC inhibitors parallels the increase of acetylation of histone 3. |
Product Citations (7)
Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. [Bantscheff M, et al. Nat Biotechnol 2011;29(3):255-65]
Inhibitors of Histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. [Huang Y, et al. Breast Cancer Res Treat 2011;131(3):777-89]
Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination. [Tang H, et al. Gene Ther 2013;20(7):770-8]
