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PANOBINOSTAT

by Selleckchem | Mar 19 2012

Introduction: Inhibition of HDAC

Of the 18 isoforms of the histone deacetylase enzyme the class one and class two proteins are the most frequently found to be over expressed in tumor tissue [1;2]. The activity of the HDAC enzyme is to remove an acetyl group from a target protein which induces a conformational change so that further protein binding is induced or inhibited. The signal begins in the cellular cytosole and is transmitted to the nucleus. This signaling transfer results eventually in the regulation of a cellular growth activity, be that life or death! The class 1 & 2 enzymes function by binding their target protein to a binding domain which has a zinc atom as a functional part. This zinc atom catalysis the deacetylation process and is the target of inhibition for most known HDAC inhibitors. [3;4]

Panobinostat is a small molecule inhibitor that has demonstrated pan-HDAC activity with known IC50’s against HDAC’s 1-9 ranging between 3 – 61 nM (note HDAC 8 is the exception which has a IC50 of 248 nM). Panobinostat has demonstrated during the initial screening the ability to inhibit tumor cell proliferation and to induce apoptosis in cells of breast cancer and T cell lymphoma [5;6].

Panobinostat: Properties and Availability

Developed by the pharmaceutical company Novartis it has been on the market for a relatively short time. Prior to being known as Panobinostat it was researched under the code name LBH589. Literature reports that Panobinostat structure is based on a hydroxycinnamamide core wit substituted methlindolyl side chains [7]. To determine that activity of pinobinostat it was screened against a panel of kinases, it demonstrated activity for HDAC enzymes but literature does not specify which HDAC’s it has activity against, reported Panobinostat IC50 against purified HDAC is listed as ± 50 nM. Panobinostat stability is recorded on the MSDS for its powered form, this is relatively stable if kept at -20°C, and again the recommended expiration date is listed as 2 years. In buffer solutions Panobinostat solubility is very poor but it will dissolve in both DMSO and ethanol to maximal concentrations of 200 and 5 mg/ml respectively. Researchers can buy Panobinostat from a variety of Panobinostat suppliers although Panobinostat cost is dependent on the supplier. Panobinostat price of a 5 mg vial range quite dramatically from $42 up to $895; researchers are advised to shop very carefully for this product.

Panobinostat: Preclinical investigations and clinical status

Panobinostat is a pan-HDAC inhibitor and is being investigated both pre-clinically and clinically against a variety of different tumor types. It is reported that the activity of Panobinostat against various growth processes occurs at concentration well below the known toxic concentration. Activity has been demonstrated in vasculogenesis, phosphorylation, endothelial tube formation and inhibition of the AKt pathway [8]. In combination with TRAIL (a known chemotherapy agent) Panobinostat has been demonstrated to increase the sensitivity of the cell lines towards TRAIL induced apoptosis [9]. Interestingly the cell lines respond most significantly were derived from pancreatic and mesothelioma cancers. In a separate study Panobinostat is reported to have induced conformational changes in protein structure which induced cell death, the cell lines used here were derived from breast cancer [10]. In relation to the heat shock protein (HSP90) HDAC inhibition was demonstrated in lung cancer cell lines to induce acetylation which resulted in EGFR depletion / apoptosis [11]. In a study continuing the investigation into the relationship of Panobinostat with HSP90 proteins it was observed that significant activity in AML and CML cell lines resulted from the combinational use of HSP90 inhibitors [12]. Further combinational investigations showed significant anti-tumor effects with rapamycin in xenografts models. In prostate, renal cell carcinoma and endothelial cells the same combination induced apoptotic effects [13].

Clinically Panobinostat has been trialed at phase I with acute myeloid leukemia patients, toxicity was determined to be minimal while the anti tumor activity was observable [14]. In direct contrast a combination with gemcitabine demonstrated significant toxicity in patient with various solid tumors but patients did respond to treatment with a number of sable diseases [15-17]. In a separate comparison study with docetaxel it was demonstrated that Panobinostat was as a single therapy compared to combination with docetaxel [18]. In recurrent glioma’s Panobinostat demonstrated anti-tumor activity registering an 80% stable disease / partial response rate prompting phase II trials to be initiated [19].

Novartis reports that Panobinostat has reached phase II status and is undergoing testing in a multitude of tumor types such as Hodgkin’s lymphoma, acute myeloid leukemia, myelodysplastic and multiple myeloid. Data for these studies is not available at this time but Novartis indicates that phase III trials will go ahead in relapsed multiple myeloid and in Hodgkin’s lymphoma.

References

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. 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.

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

5. Zhou Q, Atadja P et al. Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther 2007; 6(1):64-69.

6. Ellis L, Pan Y et al. Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res 2008; 14(14):4500-4510.

7. Beckers T, Burkhardt C et al. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int J Cancer 2007; 121(5):1138-1148.

8. Qian DZ, Kato Y et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 2006; 12(2):634-642.

9. Symanowski J, Vogelzang N et al. A histone deacetylase inhibitor LBH589 downregulates XIAP in mesothelioma cell lines which is likely responsible for increased apoptosis with TRAIL. J Thorac Oncol 2009; 4(2):149-160.

10. Rao R, Nalluri S et al. Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells. Mol Cancer Ther 2010; 9(4):942-952.

11. Edwards A, Li J et al. Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor-dependent human lung cancer cells. Mol Cancer Ther 2007; 6(9):2515-2524.

12. George P, Bali P et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 2005; 105(4):1768-1776.

13. Verheul HM, Salumbides B et al. Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 2008; 14(11):3589-3597.

14. Giles F, Fischer T et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 2006; 12(15):4628-4635.

15. Jones SF, Bendell JC et al. A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors. Clin Adv Hematol Oncol 2011; 9(3):225-230.

16. Fukutomi A, Hatake K et al. A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. Invest New Drugs 2011.

17. Morita S, Oizumi S et al. Phase I dose-escalating study of panobinostat (LBH589) Administered intravenously to Japanese patients with advanced solid tumors. Invest New Drugs 2011.

18. Rathkopf D, Wong BY et al. A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 2010; 66(1):181-189.

19. Drappatz J, Lee EQ et al. Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma. J Neurooncol 2011.