Panobinostat
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MedKoo CAT#: 202151

CAS#: 404950-80-7 (free base)

Description: Panobinostat, also known as NVP LBH-589 or LBH-589, is a cinnamic hydroxamic acid analogue with potential antineoplastic activity. Panobinostat selectively inhibits histone deacetylase (HDAC), inducing hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. In addition, this agent appears to modulate the expression of angiogenesis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF), thus impairing endothelial cell chemotaxis and invasion. On 2/23/2015, 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.


Chemical Structure

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Panobinostat
CAS# 404950-80-7 (free base)

Theoretical Analysis

MedKoo Cat#: 202151
Name: Panobinostat
CAS#: 404950-80-7 (free base)
Chemical Formula: C21H23N3O2
Exact Mass: 349.17903
Molecular Weight: 349.43
Elemental Analysis: C, 72.18; H, 6.63; N, 12.03; O, 9.16

Price and Availability

Size Price Availability Quantity
100.0mg USD 110.0 Ready to ship
200.0mg USD 190.0 Ready to ship
500.0mg USD 350.0 Ready to ship
1.0g USD 550.0 Ready to ship
2.0g USD 950.0 Ready to ship
5.0g USD 1950.0 Ready to ship
10.0g USD 2950.0 Ready to ship
20.0g USD 5250.0 2 Weeks
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Related CAS #: 960055-56-5 (lactate)   404950-80-7 (free base)   960055-50-9 (acetate)   960055-60-1 (mesylate)   960055-54-3 (fumarate)   960055-57-6 (maleate)    

Synonym: LBH589; LBH 589; LBH-589; NVP-LBH589; NVP-LBH 589; Panobinostat; trade name Farydak;

IUPAC/Chemical Name: (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

InChi Key: FPOHNWQLNRZRFC-ZHACJKMWSA-N

InChi Code: 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+

SMILES Code: O=C(NO)/C=C/C1=CC=C(CNCCC2=C(C)NC3=C2C=CC=C3)C=C1

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Panobinostat (LBH589, NVP-LBH589) is a novel broad-spectrum HDAC inhibitor with IC50 of 5 nM in a cell-free assay.
In vitro activity: Two model human Ph(-) ALL cell lines (T-cell MOLT-4 and pre-B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC(50): 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph(-) ALL cells, including those from a relapsed patient, inducing loss of cell viability (up to 70%) and induction of GADD45G mRNA expression (up to 35-fold). Thus, LBH589 possesses potent growth inhibitory activity against including Ph(-) ALL cells associated with up-regulation of genes critical for DNA damage response and growth arrest. These findings provide a rationale for exploring the clinical activity of LBH589 in the treatment of patients with Ph(-) ALL. Reference: Blood. 2008 May 15;111(10):5093-100. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18349321/ Reference: Mol Cancer Ther. 2009 Aug;8(8):2221-31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605895/
In vivo activity: In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in small cell lung cancer (SCLC) xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X(L). These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC. Reference: Mol Cancer Ther. 2009 Aug;8(8):2221-31. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19671764/ Reference: Retrovirology. 2016 May 21;13(1):36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875645/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 33.0 94.4

Preparing Stock Solutions

The following data is based on the product molecular weight 349.43 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Crisanti MC, Wallace AF, Kapoor V, Vandermeers F, Dowling ML, Pereira LP, Coleman K, Campling BG, Fridlender ZG, Kao GD, Albelda SM. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Mol Cancer Ther. 2009 Aug;8(8):2221-31. doi: 10.1158/1535-7163.MCT-09-0138. Epub 2009 Aug 11. PMID: 19671764; PMCID: PMC3605895. 2. Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P, Pullarkat V, Bhatia R, Forman S, Yen Y, Jove R. The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells. Blood. 2008 May 15;111(10):5093-100. doi: 10.1182/blood-2007-10-117762. Epub 2008 Mar 18. PMID: 18349321; PMCID: PMC2384136. 3. Crisanti MC, Wallace AF, Kapoor V, Vandermeers F, Dowling ML, Pereira LP, Coleman K, Campling BG, Fridlender ZG, Kao GD, Albelda SM. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Mol Cancer Ther. 2009 Aug;8(8):2221-31. doi: 10.1158/1535-7163.MCT-09-0138. Epub 2009 Aug 11. PMID: 19671764; PMCID: PMC3605895. 4. Tsai P, Wu G, Baker CE, Thayer WO, Spagnuolo RA, Sanchez R, Barrett S, Howell B, Margolis D, Hazuda DJ, Archin NM, Garcia JV. In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection. Retrovirology. 2016 May 21;13(1):36. doi: 10.1186/s12977-016-0268-7. PMID: 27206407; PMCID: PMC4875645.
In vitro protocol: 1. Crisanti MC, Wallace AF, Kapoor V, Vandermeers F, Dowling ML, Pereira LP, Coleman K, Campling BG, Fridlender ZG, Kao GD, Albelda SM. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Mol Cancer Ther. 2009 Aug;8(8):2221-31. doi: 10.1158/1535-7163.MCT-09-0138. Epub 2009 Aug 11. PMID: 19671764; PMCID: PMC3605895. 2. Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P, Pullarkat V, Bhatia R, Forman S, Yen Y, Jove R. The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells. Blood. 2008 May 15;111(10):5093-100. doi: 10.1182/blood-2007-10-117762. Epub 2008 Mar 18. PMID: 18349321; PMCID: PMC2384136.
In vivo protocol: 1. Crisanti MC, Wallace AF, Kapoor V, Vandermeers F, Dowling ML, Pereira LP, Coleman K, Campling BG, Fridlender ZG, Kao GD, Albelda SM. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Mol Cancer Ther. 2009 Aug;8(8):2221-31. doi: 10.1158/1535-7163.MCT-09-0138. Epub 2009 Aug 11. PMID: 19671764; PMCID: PMC3605895. 2. Tsai P, Wu G, Baker CE, Thayer WO, Spagnuolo RA, Sanchez R, Barrett S, Howell B, Margolis D, Hazuda DJ, Archin NM, Garcia JV. In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection. Retrovirology. 2016 May 21;13(1):36. doi: 10.1186/s12977-016-0268-7. PMID: 27206407; PMCID: PMC4875645.

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1: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548331/ PubMed PMID: 31643653.

2: Moore DC, Arnall JR, Harvey RD. Incidence and management of adverse events associated with panobinostat in the treatment of relapsed/refractory multiple myeloma. J Oncol Pharm Pract. 2019 Apr;25(3):613-622. doi: 10.1177/1078155218788706. Epub 2018 Jul 31. Review. PubMed PMID: 30060709.

3: Cavenagh JD, Popat R. Optimal Management of Histone Deacetylase Inhibitor-Related Adverse Events in Patients With Multiple Myeloma: A Focus on Panobinostat. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):501-507. doi: 10.1016/j.clml.2018.05.007. Epub 2018 May 24. Review. PubMed PMID: 29804873.

4: Tzogani K, van Hennik P, Walsh I, De Graeff P, Folin A, Sjöberg J, Salmonson T, Bergh J, Laane E, Ludwig H, Gisselbrecht C, Pignatti F. EMA Review of Panobinostat (Farydak) for the Treatment of Adult Patients with Relapsed and/or Refractory Multiple Myeloma. Oncologist. 2018 May;23(5):631-636. doi: 10.1634/theoncologist.2017-0301. Epub 2017 Nov 30. Review. Erratum in: Oncologist. 2018 Jul;23(7):870. PubMed PMID: 29192015; PubMed Central PMCID: PMC5947444.

5: Singh A, Patel P, Jageshwar, Patel VK, Jain DK, Kamal M, Rajak H. The Safety, Efficacy and Therapeutic Potential of Histone Deacetylase Inhibitors with Special Reference to Panobinostat in Gastrointestinal Tumors: A Review of Preclinical and Clinical Studies. Curr Cancer Drug Targets. 2018;18(8):720-736. doi: 10.2174/1568009617666170630124643. Review. PubMed PMID: 28669336.

6: Van Veggel M, Westerman E, Hamberg P. Clinical Pharmacokinetics and Pharmacodynamics of Panobinostat. Clin Pharmacokinet. 2018 Jan;57(1):21-29. doi: 10.1007/s40262-017-0565-x. Review. PubMed PMID: 28667459.

7: panobinostat (FARYDAK°). Multiple myeloma: too toxic! Prescrire Int. 2016 Nov;25(176):257-259. Review. PubMed PMID: 30715819.

8: San-Miguel JF, Einsele H, Moreau P. The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective. Adv Ther. 2016 Nov;33(11):1896-1920. Epub 2016 Sep 27. Review. PubMed PMID: 27677481; PubMed Central PMCID: PMC5083773.

9: Sivaraj D, Green MM, Gasparetto C. Panobinostat for the management of multiple myeloma. Future Oncol. 2017 Mar;13(6):477-488. doi: 10.2217/fon-2016-0329. Epub 2016 Oct 25. Review. PubMed PMID: 27776419.

10: Suresh PS, Devaraj VC, Srinivas NR, Mullangi R. Review of bioanalytical assays for the quantitation of various HDAC inhibitors such as vorinostat, belinostat, panobinostat, romidepsin and chidamine. Biomed Chromatogr. 2017 Jan;31(1). doi: 10.1002/bmc.3807. Epub 2016 Sep 13. Review. PubMed PMID: 27511598.

11: Morabito F, Voso MT, Hohaus S, Gentile M, Vigna E, Recchia AG, Iovino L, Benedetti E, Lo-Coco F, Galimberti S. Panobinostat for the treatment of acute myelogenous leukemia. Expert Opin Investig Drugs. 2016 Sep;25(9):1117-31. doi: 10.1080/13543784.2016.1216971. Epub 2016 Aug 8. Review. PubMed PMID: 27485472.

12: Redic KA, Hough SM, Price EM. Clinical developments in the treatment of relapsed or relapsed and refractory multiple myeloma: impact of panobinostat, the first-in-class histone deacetylase inhibitor. Onco Targets Ther. 2016 May 10;9:2783-93. doi: 10.2147/OTT.S87962. eCollection 2016. Review. PubMed PMID: 27274274; PubMed Central PMCID: PMC4869663.

13: Liu JD, Sun CY, Tang L, Wu YY, Wang QY, Hu B, Hu Y. Efficacy and Safety of Panobinostat in Relapsed or/and Refractory Multiple Myeloma: Meta Analyses of Clinical Trials and Systematic Review. Sci Rep. 2016 Jun 7;6:27361. doi: 10.1038/srep27361. Review. PubMed PMID: 27270478; PubMed Central PMCID: PMC4895230.

14: Srinivas NR. Clinical pharmacokinetics of panobinostat, a novel histone deacetylase (HDAC) inhibitor: review and perspectives. Xenobiotica. 2017 Apr;47(4):354-368. doi: 10.1080/00498254.2016.1184356. Epub 2016 May 25. Review. PubMed PMID: 27226420.

15: Wahaib K, Beggs AE, Campbell H, Kodali L, Ford PD. Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma. Am J Health Syst Pharm. 2016 Apr 1;73(7):441-50. doi: 10.2146/ajhp150487. Review. PubMed PMID: 27001985.

16: Greig SL. Panobinostat: A Review in Relapsed or Refractory Multiple Myeloma. Target Oncol. 2016 Feb;11(1):107-14. doi: 10.1007/s11523-015-0413-6. Review. PubMed PMID: 26826025.

17: Singh A, Patel VK, Jain DK, Patel P, Rajak H. Panobinostat as Pan-deacetylase Inhibitor for the Treatment of Pancreatic Cancer: Recent Progress and Future Prospects. Oncol Ther. 2016;4(1):73-89. doi: 10.1007/s40487-016-0023-1. Epub 2016 Jun 10. Review. PubMed PMID: 28261641; PubMed Central PMCID: PMC5315073.

18: Afifi S, Michael A, Azimi M, Rodriguez M, Lendvai N, Landgren O. Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat. Pharmacotherapy. 2015 Dec;35(12):1173-88. doi: 10.1002/phar.1671. Review. PubMed PMID: 26684557; PubMed Central PMCID: PMC4995883.

19: Bailey H, Stenehjem DD, Sharma S. Panobinostat for the treatment of multiple myeloma: the evidence to date. J Blood Med. 2015 Oct 8;6:269-76. doi: 10.2147/JBM.S69140. eCollection 2015. Review. PubMed PMID: 26504410; PubMed Central PMCID: PMC4603728.

20: Richardson PG, Harvey RD, Laubach JP, Moreau P, Lonial S, San-Miguel JF. Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes. Expert Rev Clin Pharmacol. 2016;9(1):35-48. doi: 10.1586/17512433.2016.1096773. Epub 2015 Oct 26. Review. PubMed PMID: 26503877.



Additional Information

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 studies were all resistant to the effects of chemotherapy – as are many pancreatic tumors. see http://en.wikipedia.org/wiki/Panobinostat.