Introduction: HDAC inhibition

In humans, histone deacetylase (HDAC) is a regulatory enzyme located both in the cellular cytoplasm and in the nucleus. Its function is the removal of an acetyl group from both protein and non-protein targets, this removal is usually part of a signaling pathway inducing or reducing various activities within the cell. There are currently 18 isoforms of HDAC known which are classified into four classes. Class 1 are the nucleus HDAC´s (1,2,3&8) [1;2]; Class II HDAC´s (4, 5, 7 & 9) are located in either the cytoplasm, the nuclease or a transitional state between the two [1]. These two classes of enzymes are related by the fact that they require a zinc catalyst for activity [3]. Class III (6&10) and IV HDAC´s (11) do not require zinc for their activity but instead rely on NAD+ for their activity [4;5].

In the field of HDAC inhibition Belinostat is rather unique, actively inhibiting HDAC cellular signaling Belinostat restarts normal cellular apoptotic function via the TGRßRII (tumor suppressor gene transforming growth factor ß) pathway [6]. Success of this molecule and the uniqueness of it mechanism of action has led to the molecule receiving orphan drug status and fast track approval for its action o T-Cell lymphoma [7].'

Belinostat (PXD101) Chemical Structure

Belinostat: Properties and Availability

The Belinostat HDAC inhibitor is a relatively new molecule and under development by TopoTarget A/S and Spectrum pharmaceuticals since 2008. The Belinostat structure is based on hydroxamic acid with an adapted side chain that increases its specificity and potency compared to the original molecule. Testing this against HDAC class I and class II proteins the BELINOSTAT IC50’s indicated that it is a potent inhibitor of both classes of HDAC’s with values ranging from 40 -200 nM; the most sensitive HDAC’s were 1, 3 & 7 [8]. BELINOSTAT solubility in water and ethanol is unknown but BELINOSTAT is soluble in DMSO but no details .are listed with regard to this chemical. BELINOSTAT stability is listed for its powdered form and this can be stored for upwards of 2 years if kept at -20oC or below. Researchers can buy BELINOSTAT from a variety of BELINOSTAT suppliers although BELINOSTAT cost is dependent on the supplier. BELINOSTAT price of a 10 mg vial can range from $150 up to $450; researchers are advised to shop very carefully for this product.

Belinostat: Pre-clinical investigations and clinical status

Pre-clinically Belinostat has been tested in a panel of ovarian cell lines demonstrating clear antitumor activity [9]. Belinostat was demonstrated as having single agent effect of ovarian cancer cell lines which was enhanced with the use of carboplatin. In an murine model of prostate cancer Belinostat was seen to prevent metastatic activity in the lung from a liver cancer model. It also reduced tumor size in 43% of the subjects tested [10]. In a phase II in solid tumors, the tumor volumetrics was correlated to disease status; significant differences were observed for Belinostat showing activity and response that was masked by the strictures of the RECIST criteria. In Acute myeloid leukemia cells a combination of belinostat and bortezomib demonstrated a synergistic profile [11].

At phase I level Belinostat has been report in conjunction with advanced solid tumors [12], advanced hametological neoplasia [13], liver cancer [14], in combination with carboplatin and paclitaxel treatment of solid tumors [15] and thymic malignancies [16]. Results from these studies show that Belinostat demonstrates a broad spectrum of tumor response not only pre-clinically but also in a clinical setting. Toxicity of Belinostat appears favorable at the dose levels used, even when an IV treatment profile was performed. Belinostats ability to be administered both orally and via IV give the scheduling options greater flexibility, hence improving patient response.


   1.   Martin M, Kettmann R et al. Class IIa histone deacetylases: regulating the regulators. Oncogene 2007; 26(37):5450-5467.

   2.   Witt O, Deubzer HE et al. HDAC family: What are the cancer relevant targets? Cancer Lett 2009; 277(1):8-21.

   3.   Jurkin J, Zupkovitz G et al. Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis. Cell Cycle 2011; 10(3):406-412.

   4.   Codd R, Braich N et al. Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol 2009; 41(4):736-739.

   5.   Rajendran P, Williams DE et al. Metabolism as a key to histone deacetylase inhibition. Crit Rev Biochem Mol Biol 2011; 46(3):181-199.

   6.   Chowdhury S, Howell GM et al. Histone deacetylase inhibitor belinostat represses survivin expression through reactivation of transforming growth factor beta (TGFbeta) receptor II leading to cancer cell death. J Biol Chem 2011; 286(35):30937-30948.

   7.   Tan J, Cang S et al. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol 2010; 3:5.

   8.   Khan N, Jeffers M et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 2008; 409(2):581-589.

   9.   Qian X, LaRochelle WJ et al. Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Cancer Ther 2006; 5(8):2086-2095.

10.   Qian X, Ara G et al. Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Cancer 2008; 122(6):1400-1410.

11.   Dai Y, Chen S et al. Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbation in NF-kappaB and Bim. Br J Haematol 2011.

12.   Steele NL, Plumb JA et al. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res 2008; 14(3):804-810.

13.   Gimsing P, Hansen M et al. A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur J Haematol 2008; 81(3):170-176.

14.   Wang LZ, Chan D et al. A sensitive and specific liquid chromatography-tandem mass spectrometric method for determination of belinostat in plasma from liver cancer patients. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878(26):2409-2414.

15.   Lassen U, Molife LR et al. A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours. Br J Cancer 2010; 103(1):12-17.

16.   Force J, Rajan A et al. Assessment of objective responses using volumetric evaluation in advanced thymic malignancies and metastatic non-small cell lung cancer. J Thorac Oncol 2011; 6(7):1267-1273.

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