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| IUPAC_name = (2''E'')-''N''-hydroxy-3-[4-({[2-(2-methyl-1''H''-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide
| IUPAC_name = (2''E'')-''N''-hydroxy-3-[4-({[2-(2-methyl-1''H''-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide
| image = Panobinostat structure.svg
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| tradename = Farydak
| tradename = Farydak

Revision as of 15:12, 8 April 2015

Panobinostat
Clinical data
Trade namesFarydak
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability21%[1]
Protein binding90%[1]
MetabolismCYP3A (40%), CYP2D6, CYP2C19[1]
Elimination half-life37 hours[1]
ExcretionFecal (44–77%), renal (29–51%)[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC21H23N3O2
Molar mass349.42622 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Panobinostat (LBH-589, trade name Farydak) is a drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid[2] and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).[3]

On 23 February 2015 it received FDA accelerated approval for use in patients with multiple myeloma who had received at least 2 previous treatments, including bortezomib and an immunomodulatory agent."[4] after clinical trials.[5]

Clinical trials

As of August 2012, it is being tested against Hodgkin's Lymphoma, cutaneous T cell lymphoma (CTCL)[6] 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.[7][8]

As of 2014 Panobinostat is 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.[9][10] [11]

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.[12]

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.[13]

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.[14]

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.[15]

Mechanism of action

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.[2]

References

  1. 1.0 1.1 1.2 1.3 1.4 Panobinostat Package Insert
  2. 2.0 2.1 Revill, P; Mealy, N; Serradell, N; Bolos, J; Rosa, E (2007). "Panobinostat". Drugs of the Future. 32 (4): 315. doi:10.1358/dof.2007.032.04.1094476. ISSN 0377-8282.
  3. Table 3: Select epigenetic inhibitors in various stages of development from Template:Cite doi
  4. FDA.gov announcement about accelerated approval of panobinostat (Farydak)
  5. Panobinostat chemotherapy regimen for multiple myeloma (MM wiki)
  6. Clinical trial number NCT00425555 for "Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma" at ClinicalTrials.gov
  7. ClinicalTrials.gov: LBH-589
  8. 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.
  9. Simons, J (27 April 2013). "Scientists on brink of HIV cure". The Telegraph.
  10. Clinical trial number NCT01680094 for "Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART (CLEAR)" at ClinicalTrials.gov
  11. Template:Cite doi
  12. Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells
  13. 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. doi:10.1093/hmg/ddp313. PMID 19584083.
  14. 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).
  15. 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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