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Panobinostat

Panobinostat
Systematic (IUPAC) name
(2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide
Clinical data
Trade names Faridak
Legal status
  • Experimental
Routes Oral
Identifiers
CAS number  YesY
ATC code L01
PubChem
ChemSpider  N
UNII  YesY
KEGG  N
Chemical data
Formula C21H23N3O2 
Mol. mass 349.42622 g/mol
 N   

Panobinostat (LBH-589, trade name Faridak) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor).[2]

Contents

  • Clinical trials 1
  • Preclinical studies 2
  • Mechanism of action 3
  • References 4

Clinical trials

As of August 2012, it is being tested against Hodgkin's Lymphoma, cutaneous T cell lymphoma (CTCL)[3] and other types of malignant disease in Phase III clinical trials, against myelodysplastic syndromes, breast cancer and prostate cancer in Phase II trials, and against chronic myelomonocytic leukemia (CMML) in a Phase I trial.[4][5]

Panobinostat is currently being used in a Phase I/II clinical trial that aims at curing AIDS in patients on highly active antiretroviral therapy (HAART). In this technique, panobinostat is used to drive the HIV DNA out of the patient's DNA, in the expectation that the patient's immune system in combination with HAART will destroy it.[6][7] [8]

Preclinical studies

Panobinostat has been found to synergistically act with sirolimus to kill pancreatic cancer cells in the laboratory in a Mayo Clinic study. In the study, investigators found that this combination destroyed up to 65 percent of cultured pancreatic tumor cells. The finding is significant because the three cell lines studied were all resistant to the effects of chemotherapy – as are many pancreatic tumors.[9]

Panobinostat has also been found to significantly increase in vitro the survival of motor neuron (SMN) protein levels in cells of patients suffering from spinal muscular atrophy.[10]

Panobinostat was able to selectively target triple negative breast cancer (TNBC) cells by inducing hyperacetylation and cell cycle arrest at the G2-M DNA damage checkpoint; partially reversing the morphological changes characteristic of breast cancer cells.[11]

Panobinostat, along with other HDAC inhibitors, is also being studied for potential to induce virus HIV-1 expression in latently infected cells and disrupt latency. These resting cells are not recognized by the immune system as harboring the virus and do not respond to antiretroviral drugs.[12]

Mechanism of action

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.[1]

References

  1. ^ a b Revill, P; Mealy, N; Serradell, N; Bolos, J; Rosa, E (2007). "Panobinostat". Drugs of the Future 32 (4): 315.  
  2. ^ Table 3: Select epigenetic inhibitors in various stages of development from Mack, G. S. (2010). "To selectivity and beyond". Nature Biotechnology 28 (12): 1259–1266.  
  3. ^ ClinicalTrials.gov NCT00425555 Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma
  4. ^ ClinicalTrials.gov: LBH-589
  5. ^ Prince, HM; M Bishton (2009). "Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma". Hematology Meeting Reports (Parkville, Australia: Peter MacCallum Cancer Centre and University of Melbourne) 3 (1): 33–38. 
  6. ^ Simons, J (27 April 2013). "Scientists on brink of HIV cure". The Telegraph. 
  7. ^ ClinicalTrials.gov NCT01680094 Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART (CLEAR)
  8. ^ Rasmussen, T. A.; Tolstrup, M.; Brinkmann, C. R.; Olesen, R.; Erikstrup, C.; Solomon, A.; Winckelmann, A.; Palmer, S.; Dinarello, C.; Buzon, M.; Lichterfeld, M.; Lewin, S. R.; Østergaard, L.; Søgaard, O. S. (2014). "Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: A phase 1/2, single group, clinical trial". The Lancet HIV 1: e13.  
  9. ^ Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells
  10. ^ Garbes, L; Riessland, M; Hölker, I; Heller, R; Hauke, J; Tränkle, Ch; Coras, R; Blümcke, I; Hahnen, E; Wirth, B (2009). "LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate". Human Molecular Genetics 18 (19): 3645–3658.  
  11. ^ Tate, CR; Rhodes, LV; Segar, HC; Driver, JL; Pounder, FN; Burow, ME; Collins-Burow, BM (2012). "Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat". Breast Cancer Research 14 (3). 
  12. ^ TA Rasmussen, et al. Comparison of HDAC inhibitors in clinical development: Effect on HIV production in latently infected cells and T-cell activation. Human Vaccines & Immunotherapeutics 9:5, 1-9, May 2013.
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