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 dose of Belinostat is excreted by the kidneys, primarily as metabolites, with less than 2% of the total dose recovered unchanged. Volume of distribution: 409 ± 76.7 L. Outflow rate: 1240 mL/min Metabolism/Metabolites Primarily metabolized by hepatic UGT1A1. Potent UGT1A1 inhibitors are expected to increase Belinostat exposure. Belinostat can also be metabolized by hepatic CYP2A6, CYP2C9, and CYP3A4 enzymes to Belinostatamide and Belinostatic acid. The enzymes responsible for the formation of methylbenilinostat and 3-(anilinesulfonyl)benzoic acid (3-ASBA) are unknown. Biological half-life Exhibits three-compartment pharmacokinetics with an elimination half-life of 1.1 hours.

Hepatotoxicity
In clinical trials of Belinostat in patients with PTCL, the incidence of elevated serum enzymes during treatment was generally less than 5%, with only 1% to 2% of patients experiencing serum enzyme levels exceeding five times the upper limit of normal. In an open-label trial of Belinostat monotherapy in 120 patients with PTCL, a case of severe acute liver injury leading to liver failure and death was reported. This liver injury occurred after 10 cycles of treatment and continued to progress despite discontinuation of the drug. No specific details were provided. Two cases of cholestatic liver injury were reported in another clinical trial, but similarly, no specific details were provided. Therefore, Belinostat is considered a rare cause of acute liver injury, but its onset time, related characteristics, clinical course, and prognosis remain unclear. Probability score: D (likely a clinically significant cause of liver injury). Protein Binding Belinostat has a protein binding rate of 92.9% to 95.8%.

[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 histone deacetylase (HDAC) inhibitor with antitumor activity. It is both an antitumor drug and an EC 3.5.1.98 (histone deacetylase) inhibitor. It is a hydroxamic acid, sulfonamide, and olefin compound. Belinostat is a novel drug with a sulfonamide-hydroxamic acid structure that inhibits histone deacetylase (HDAC). Developed by TopoTarget, it is intended as an orphan drug for the treatment of hematologic malignancies and solid tumors. The safety and efficacy of Belinostat in combination with conventional first-line therapy for the treatment of peripheral T-cell lymphoma (PTCL) are currently being evaluated. The drug is administered intravenously under the brand name Beleodaq and can be used as monotherapy in a 21-day cycle. Belinostat was approved in the United States in July 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma. Belinostat is a histone deacetylase inhibitor. Belinostat's mechanism of action is the inhibition of histone deacetylase. Belinostat is an intravenously administered histone deacetylase inhibitor and antitumor drug approved for the treatment of refractory or relapsed peripheral T-cell lymphoma. Belinostat can cause moderate to mild elevations in serum enzymes during treatment, and there are reports of clinically significant and potentially fatal acute liver injury. Belinostat is a novel hydroxamic acid histone deacetylase (HDAC) inhibitor with antitumor activity. Belinostat targets HDAC enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cell differentiation, and inhibiting angiogenesis. This drug may enhance the sensitivity of drug-resistant tumor cells to other antitumor drugs by downregulating thymidylate synthase.

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Drug Indications
Belinostat is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) with a good safety profile. For patients who have not responded well to first-line PTCL therapies, Belinostat is a potential alternative therapy. This drug can also be used in patients with baseline thrombocytopenia.
FDA Label

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Mechanism of Action
Belisitar inhibits the activity of histone deacetylase (HDAC), thereby preventing the removal of acetyl groups from histone and certain non-histone lysine residues. In vitro studies have shown that belisitar leads to the accumulation of acetylated histones and other proteins, and increases the expression of tumor suppressor genes. It ultimately induces cell cycle arrest, inhibits angiogenesis, and/or causes apoptosis in certain 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.)