Belinostat(PXD101)

• Catalog No.: S1085
• CAS Number: 414864-00-9
• M. F.: C15H14N2O4S
• M. W.: 318.34766
• Storage: -20°C

SYNONYMS

• IUPAC name: (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide
• IUPAC Traditional name: (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide
• Synonyms: PXD101; PX105684

DATABASE IDS

• CAS Number: 414864-00-9

PROPERTIES

• Target: HDAC
• Salt Data: Free Base
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Thymoma,Mesothelioma, Acute myeloid leukaemia

Biological Activity

• Description: Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM in HeLa cell extracts.
• 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]
• Clinical Trials: Belinostat is currently in Phase II clinical trial in patients with relapsed or refractory peripheral T-cell lymphoma.
• Features: Lead compound of Topotarget

Protocol

• Protocol: 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 × 10^4 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 cent
• Protocol: Cell Assay ^[1]
• Cell lines: A2780, A2780/cp70, 2780AD, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852
• 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.
• Protocol: Animal Study ^[1]
• Animal Models: A2780, A2780/cp70 and HCT116 cells are injected s.c. into the right flank of CD1 nu/nu mice.
• Formulation: Dissolved in DMSO and then diluted in water to give a final concentration of DMSO of 10%
• Doses: ≤40 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Plumb JA, et al. Mol Cancer Ther, 2003, 2(8), 721-728.
• References: [2] Buckley MT, et al. J Transl Med, 2007, 5:49.
• References: [3] Qian X, et al. Mol Cancer Ther, 2006, 5(8), 2086-2095.
• References: [4] Chowdhury S, et al. J Biol Chem, 2011, 286(35), 30937-30948.
• References: [5] Duan J, et al. Mol Cancer Ther, 2007, 6(1), 37-50.

REFERENCES

• Plumb JA, et al. Mol Cancer Ther, 2003, 2(8), 721-728.
• Buckley MT, et al. J Transl Med, 2007, 5:49.
• Qian X, et al. Mol Cancer Ther, 2006, 5(8), 2086-2095.
• Chowdhury S, et al. J Biol Chem, 2011, 286(35), 30937-30948.
• Duan J, et al. Mol Cancer Ther, 2007, 6(1), 37-50.