Panobinostat

Last updated

Panobinostat
Panobinostat.svg
Clinical data
Trade names Farydak
Other namesLBH-589
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • US: ℞-only [2]
  • EU:Rx-only [3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 21% [2]
Protein binding 90% [2]
Metabolism CYP3A (40%), CYP2D6, CYP2C19 [2]
Elimination half-life 37 hours [2]
Excretion Fecal (44–77%), renal (29–51%) [2]
Identifiers
  • (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.230.582 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H23N3O2
Molar mass 349.434 g·mol−1
3D model (JSmol)
  • O=C(NO)\C=C\c1ccc(cc1)CNCCc3c2ccccc2[nH]c3C
  • InChI=1S/C21H23N3O2/c1-15-18(19-4-2-3-5-20(19)23-15)12-13-22-14-17-8-6-16(7-9-17)10-11-21(25)24-26/h2-11,22-23,26H,12-14H2,1H3,(H,24,25)/b11-10+ X mark.svgN
  • Key:FPOHNWQLNRZRFC-ZHACJKMWSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. [2] [3] It is a hydroxamic acid [4] and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor). [5]

Contents

Panobinostat was approved for medical use in the United States in February 2015, [2] [6] [7] and in the European Union in August 2015. [3] [8] However, in March 2022, it was withdrawn in the United States. [9] [10]

Medical uses

Panobinostat is used in combination with the anti-cancer drug bortezomib and the corticoid dexamethasone for the treatment of multiple myeloma in adults who had received at least two previous treatments, including bortezomib and an immunomodulatory agent. [2] [11] : 660 

Contraindications

Panobinostat is contraindicated in nursing mothers. To judge from experiments in animals, there is a risk for the unborn child if used during pregnancy; still, the benefit of panobinostat may outweigh this risk. [12]

Side effects

Common side effects (in more than 10% of patients) include low blood cell counts (pancytopenia, thrombocytopenia, anaemia, leucopenia, neutropenia, lymphopenia), airway infections, as well as unspecific reactions such as fatigue, diarrhoea, nausea, headache, and sleeping problems. [12]

Pharmacology

Mechanism of action

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways. [4]

Pharmacokinetics

Panobinostat is absorbed quickly and almost completely from the gut, but has a significant first-pass effect, resulting in a total bioavailability of 21%. Highest blood plasma levels in patients with advanced cancer are reached after two hours. Plasma protein binding is about 90%. The substance is metabolised mainly through oxidation by the liver enzyme CYP3A4 and to a small extent by CYP2D6 and CYP2C19. It is also reduced, hydrolyzed and glucuronidized by unspecified enzymes. All metabolites seem to be inactive. [12]

Biological half-life is estimated to be 37 hours. 29–51% are excreted via the urine and 44–77% via the faeces. [12]

Clinical trials

As of August 2012, it is being tested against Hodgkin's Lymphoma, cutaneous T cell lymphoma (CTCL) [13] 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. [14] [15]

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. [16] [17] [18]

As of 2016 panobinostat is being studied in a phase II trial for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). [19]

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. [20]

Panobinostat has also been found to significantly increase in vitro the survival of motor neuron (SMN) protein levels in cells of patients with spinal muscular atrophy. [21]

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. [22]

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. [23]

A 2015 study suggested Panobinostat was effective in preventing diffuse intrinsic pontine glioma cell growth in vitro and in vivo, identifying it as a potential drug candidate. [24]

Panobinostat was also identified as a senolytic, effective at killing senescent cells. [25]


Related Research Articles

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

<span class="mw-page-title-main">Trichostatin A</span> Chemical compound

Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs. However, there are recent reports of the interactions of this molecule with Sirt 6 protein. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors that have a broad spectrum of epigenetic activities. Thus, TSA has some potential as an anti-cancer drug. One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer. Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.

<span class="mw-page-title-main">Tipifarnib</span> Chemical compound

Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.

Vorinostat (rINN), also known as suberoylanilide hydroxamic acid, is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

Leronlimab is a humanized monoclonal antibody targeted against the CCR5 receptor found on T lymphocytes of the human immune system. It is being investigated as a potential therapy in the treatment of COVID-19, triple negative breast cancer, and HIV infection. The United States Food and Drug Administration has designated PRO 140 for fast-track approval. In February 2008, the drug entered Phase 2 clinical trials and a phase 3 trial was begun in 2015. In February 2018, Cytodyn Inc reported that the primary endpoint had been achieved in the PRO 140 pivotal combination therapy trial in HIV infection. In 2020 CytoDyn submitted a fast-track biologics license application for treatment of CCR5-tropic HIV-1 Infection.

<span class="mw-page-title-main">TopoTarget</span>

TopoTarget was a Copenhagen-based biotechnology company focused on the discovery and development of drugs and therapies to treat cancer. In 2014, it merged with BioAlliance Pharma and is now part of Onxeo.

<span class="mw-page-title-main">Pomalidomide</span> Chemical compound

Pomalidomide, sold under the brand names Pomalyst and Imnovid, is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma.

<span class="mw-page-title-main">Romidepsin</span> Chemical compound

Romidepsin, sold under the brand name Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, a part of Celgene.

<span class="mw-page-title-main">Mocetinostat</span> Chemical compound

Mocetinostat (MGCD0103) is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers including follicular lymphoma, Hodgkin's lymphoma and acute myelogenous leukemia.

<span class="mw-page-title-main">Phosphoinositide 3-kinase inhibitor</span>

Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

Givinostat, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy. It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle.

<span class="mw-page-title-main">Abexinostat</span> Chemical compound

Abexinostat is an experimental drug candidate for cancer treatment. It was developed by Pharmacyclics and licensed to Xynomic. As of 2013, it was in Phase II clinical trials for B-cell lymphoma. Pre-clinical study suggests the potential for treatment of different types of cancer as well.

<span class="mw-page-title-main">Quisinostat</span> Chemical compound

Quisinostat is an experimental drug candidate for the treatment of cancer. It is a "second generation" histone deacetylase inhibitor with antineoplastic activity. It is highly potent against class I and II HDACs.

Resminostat is an orally bioavailable inhibitor of histone deacetylases (HDACs), of which inhibitors are antineoplastic agents.

<span class="mw-page-title-main">Tucidinostat</span> Chemical compound

Tucidinostat is a histone deacetylase inhibitor (HDI) developed in China. It was also known as HBI-8000. It is a benzamide HDI and inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10.

<span class="mw-page-title-main">Sharon Lewin</span> Australian infectious disease physician and researcher

Sharon Ruth Lewin is an Australian infectious diseases expert who is the inaugural Director of The Peter Doherty Institute for Infection and Immunity and the Cumming Global Centre for Pandemic Therapeutics. She is also a Melbourne Laureate Professor of Medicine at The University of Melbourne, and the current President of the International AIDS Society (IAS).

<span class="mw-page-title-main">Epigenetic priming</span> Type of modification to a cells epigenome

Epigenetic priming is the modification to a cell's epigenome whereby specific chromatin domains within a cell are converted from a closed state to an open state, usually as the result of an external biological trigger or pathway, allowing for DNA access by transcription factors or other modification mechanisms. The action of epigenetic priming for a certain region of DNA dictates how other gene regulation mechanisms will be able to act on the DNA later in the cell’s life. Epigenetic priming has been chiefly investigated in neuroscience and cancer research, as it has been found to play a key role in memory formation within neurons and tumor-suppressor gene activation in cancer treatment respectively.

<span class="mw-page-title-main">Zabadinostat</span> Chemical compound

Zabadinostat is an experimental epigenetic drug being investigated as a potential treatment for advanced or metastatic cancers. It is an orally available Class I selective histone deacetylase (HDAC) inhibitor, with half maximal inhibitory concentrations (IC50) of 62 nM, 570 nM and 550 nM, against HDAC1, HDAC2 and HDAC3, respectively. It shows no activity against HDAC class II.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. 1 2 3 4 5 6 7 8 9 "Farydak- panobinostat capsule". DailyMed. 27 July 2021. Retrieved 22 October 2022.
  3. 1 2 3 "Farydak EPAR". European Medicines Agency. 17 September 2018. Retrieved 22 October 2022.
  4. 1 2 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.
  5. ↑ Table 3: Select epigenetic inhibitors in various stages of development Archived 18 April 2016 at the Wayback Machine from Mack GS (December 2010). "To selectivity and beyond". Nature Biotechnology. 28 (12): 1259–66. doi:10.1038/nbt.1724. PMID   21139608. S2CID   11480326.
  6. ↑ "Farydak Drug Approval Package". U.S. Food and Drug Administration (FDA). 17 March 2015. Retrieved 22 October 2022.
  7. ↑ "Drug Trials Snapshot: Farydak (panobinostat)". U.S. Food and Drug Administration (FDA). 30 July 2020. Retrieved 22 October 2022.
  8. ↑ "Farydak product details". European Medicines Agency. 17 September 2018. Archived from the original on 20 June 2018. Retrieved 1 February 2017.
  9. ↑ "Withdrawn Oncology /Hematologic Malignancies Accelerated Approvals". U.S. Food and Drug Administration (FDA). 1 June 2022. Retrieved 22 October 2022.
  10. ↑ "Secura Bio, Inc.; Withdrawal of Approval of New Drug Application for Farydak (panobinostat) Capsules, 10 Milligrams, 15 Milligrams, and 20 Milligrams". Federal Register. 24 March 2022. Retrieved 22 October 2022.
  11. ↑ Rajkumar SV (2018). "Multiple Myeloma". In Hensley ML, Milowsky MI, Rajkumar SV, Schuetze SM (eds.). ASCO-SEP : Medical Oncology Self-Evaluation Program (7th ed.). Alexandria, VA: American Society of Clinical Oncology. ISBN   978-0-9983747-4-1. OCLC   1080368315.
  12. 1 2 3 4 Haberfeld, H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  13. ↑ Clinical trial number NCT00425555 for "Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma" at ClinicalTrials.gov
  14. ↑ "Studies found for LBH-589". ClinicalTrials.gov.
  15. ↑ Prince HM, Prince M (2009). "Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma". Hematology Meeting Reports. 3 (1). Parkville, Australia: Peter MacCallum Cancer Centre and University of Melbourne: 33–38.
  16. ↑ Simons J (27 April 2013). "Scientists on brink of HIV cure". The Telegraph. Archived from the original on 27 April 2013.
  17. ↑ 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
  18. ↑ Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, et al. (October 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 (1): e13-21. doi:10.1016/S2352-3018(14)70014-1. PMID   26423811.
  19. ↑ Hoffman J (May 2016). "Panobinostat May Be Active in Select Patients With Refractory DLBCL". CancerTherapyAdvisor.com. Archived from the original on 8 August 2016. Retrieved 23 May 2016.
  20. ↑ "Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells". The Mayo Clinic. Archived from the original on 20 February 2012.
  21. ↑ Garbes L, Riessland M, Hölker I, Heller R, Hauke J, Tränkle C, et al. (October 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): 3645–58. doi:10.1093/hmg/ddp313. PMID   19584083.
  22. ↑ Tate CR, Rhodes LV, Segar HC, Driver JL, Pounder FN, Burow ME, Collins-Burow BM (May 2012). "Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat". Breast Cancer Research. 14 (3): R79. doi: 10.1186/bcr3192 . PMC   3446342 . PMID   22613095.
  23. ↑ Rasmussen TA, Schmeltz Søgaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, et al. (May 2013). "Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation". Human Vaccines & Immunotherapeutics. 9 (5): 993–1001. doi:10.4161/hv.23800. PMC   3899169 . PMID   23370291.
  24. ↑ Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, et al. (June 2015). "Functionally defined therapeutic targets in diffuse intrinsic pontine glioma". Nature Medicine. 21 (6): 555–9. doi:10.1038/nm.3855. PMC   4862411 . PMID   25939062.
  25. ↑ Samaraweera, L., Adomako, A., Rodriguez-Gabin, A. et al. A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC. Sci Rep 7, 1900 (2017). https://doi.org/10.1038/s41598-017-01964-1/PMID: 28507307 PMCID: PMC5432488
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.