HDAC6 82 nM (IC50) HDAC 27 nM (IC50, Hela cell)

In tumor cell lines, belinostat (PXD101) causes an increase in the acetylation of histone H4 that is concentration-dependent (0.2–5 μM). A clonogenic study revealed that belinostat is cytotoxic in vitro in a variety of tumor cell lines, causing apoptosis with IC50s in the 0.2–3.4 μM range. Many human tumor cell lines are inhibited in vitro by belinostat, whose IC50s, as measured by a clonogenic experiment, fall between 0.2 and 3.4 μM[1]. The enzymatic activity of pure recombinant HDAC6 (IC50 of 82 nM) is potently inhibited by belinostat (PXD101), a strong histone deacetylase (HDAC) inhibitor[2].

For seven days, Belinostat (10–40 mg/kg/day ip) was given intraperitoneally to nude mice carrying human ovarian and colon tumor xenografts. This treatment significantly delayed the animals's growth without showing any overt evidence of harm. Cells resistant to cisplatin found in ovarian tumor xenografts also show growth retardation. Three hours following treatment with belinostat (PXD101), a significant rise in acetylation of H4 is found in the blood and tumor of mice. mice's human tumor xenografts are grown less rapidly, and there is no visible toxicity[1]. When used in combination with carboplatin therapy, belinostat (PXD101) exhibits increased single-agent antitumor efficacy on human A2780 ovarian cancer sc xenografts[2].

Absorption, Distribution and Excretion
Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites and less than 2% of total dose recovered as unchanged parent drug.
The volume of distribution is 409 ± 76.7 L.
1240 mL/min

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Metabolism / Metabolites
Primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known

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Biological Half-Life
Displays a three-compartment pharmacokinetic property with elimination half life of 1.1 hours

Hepatotoxicity
In clinical trials of belinostat in patients with PTCL, the rates of serum enzyme elevations during therapy were usually less than 5%, and were above 5 times the ULN in only 1% to 2% of patients. A single instance of severe acute liver injury leading to death from liver failure was reported in an open label trial of belinostat monotherapy in 120 patients with PTCL. The liver injury arose after 10 cycles of treatment and progressed despite drug discontinuation. Specific details were not provided. In another clinical trial, two cases of cholestatic liver injury were reported but without specific details. Thus, belinostat is considered to be a rare cause of acute liver injury but the timing of onset, associated features, clinical course and outcome have not been well defined.
Likelihood score: D (possible cause of clinically apparent liver injury).

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Protein Binding
92.9% and 95.8% of belinostat is bound to protein.

[1]. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histonedeacetylase inhibitor PXD101. Mol Cancer Ther. 2003 Aug;2(8):721-8.

[2]. Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Cancer Ther. 2006 Aug;5(8):2086-95.

[3]. Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time. Nat Commun. 2017 Sep 5;8(1):435.

Belinostat is a hydroxamic acid-type histone deacetylase (HDAC) inhibitor with antineoplastic activity. It has a role as an antineoplastic agent and an EC 3.5.1.98 (histone deacetylase) inhibitor. It is a hydroxamic acid, a sulfonamide and an olefinic compound.
Belinostat is a novel agent that inhibits the enzyme histone deacetylase (HDAC) with a sulfonamide-hydroxamide structure. It was developed as an orphan drug to target hematological malignancies and solid tumors by TopoTarget. The safety and efficacy of belinostat is currently being evaluated for use in combination with traditional front-line therapies for the treatment of PTCL. Intravenous administration of the agent is available as Beleodaq as monotherapy and the dosing regimen involves a 21-day cycle. It was US-approved in July 2014 as a therapeutic agent for relapsed or refractory peripheral T-cell lymphoma.
Belinostat is a Histone Deacetylase Inhibitor. The mechanism of action of belinostat is as a Histone Deacetylase Inhibitor.
Belinostat is an intravenously administered histone deacetylase inhibitor and antineoplastic agent that is approved for use in refractory or relapsed peripheral T cell lymphoma. Belinostat is associated with moderate rate of minor serum enzyme elevations during therapy and has been reported to cause clinically apparent fatal, acute liver injury.
Belinostat is a novel hydroxamic acid-type histone deacetylase (HDAC) inhibitor with antineoplastic activity. Belinostat targets HDAC enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis. This agent may sensitize drug-resistant tumor cells to other antineoplastic agents, possibly through a mechanism involving the down-regulation of thymidylate synthase.

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Drug Indication
Belinostat is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) with manageable safety profile. It is a potential alternative therapy for patients who did not experience adequate response to first-line drugs for PTCL. It can be used in patients with baseline thrombocytopenia.
FDA Label

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Mechanism of Action
Belinostat inhibits the activity of histone deacetylase (HDAC) thus prevents the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, increased the expression of tumor-suppressor genes. It ultimately induces cell cycle arrest, inhibition of angiogenesis and/or apoptosis of some transformed cells.

C15H14N2O4S

318.35

318.067

866323-14-0

866323-14-0; 414864-00-9;

6918638

White to off-white solid powder

160 °C(dec.)

4

3

5

5

22

492

0

C1=CC=C(C=C1)NS(=O)(=O)C2=CC=CC(=C2)/C=C/C(=O)NO

NCNRHFGMJRPRSK-MDZDMXLPSA-N

InChI=1S/C15H14N2O4S/c18-15(16-19)10-9-12-5-4-8-14(11-12)22(20,21)17-13-6-2-1-3-7-13/h1-11,17,19H,(H,16,18)/b10-9+

(E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 100 mg/mL (314.12 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.85 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)