Vorinostat

Vorinostat
Clinical data
Pronunciation /vɒˈrɪnoʊstæt/ vorr-IN-oh-stat
Trade names Zolinza
AHFS/Drugs.com Monograph
MedlinePlus a607050
License data
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration		 Oral (capsules)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 1.8–11%[1]
Protein binding ~71%
Metabolism Hepatic glucuronidation and β-oxidation
CYP system not involved
Metabolites vorinostat O-glucuronide, 4-anilino-4-oxobutanoic acid (both inactive)[2]
Biological half-life ~2 hours (vorinostat and O-glucuronide), 11 hours (4-anilino-4-oxobutanoic acid)
Excretion Renal (negligible)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.207.822
Chemical and physical data
Formula C14H20N2O3
Molar mass 264.32 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Vorinostat (rINN)[3] also known as suberanilohydroxamic acid (suberoyl+anilide+hydroxamic acid abbreviated as SAHA) 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.

Vorinostat is marketed under the name Zolinza (/zoʊˈlɪnzə/ zoh-LIN-zə) by Merck for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after two systemic therapies.[2][4] The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.[5][6]

Medical uses

Vorinostat was the first histone deacetylase inhibitor[7] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006.[8] It also failed to demonstrate efficacy in treating acute myeloid leukemia in a phase II study.[9]

Mechanism of action

Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for zinc ions also found in the active site of histone deacetylases.[10] Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation.[10]

Clinical trials

Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.[11]

A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4–4.4 months in earlier studies).[12] Further brain tumor trials are planned in which vorinostat will be combined with other drugs.

Including vorinostat in treatment of advanced non-small-cell lung carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival.[13]

It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with idarubicin and cytarabine.[14]

Preclinical investigations

Vorinostat is an interesting target for scientists interested in eradicating HIV from infected persons.[15] Vorinostat was recently shown to have both in vitro and in vivo effects against latently HIV infected T cells.[16][17]

Vorinostat also has shown some activity against the pathophysiological changes in α1-antitrypsin deficiency[18] and cystic fibrosis.[19] Recent evidences also indicate Vorinostat as a therapeutic tool for Niemann-Pick type C1 (NPC1), a rare lysosomal lipid storage disease.[20]

See also

References

  1. ↑ "Withdrawal Assessment Report for Vorinostat MSD 100 mg Hard Capsules (vorinostat)" (PDF). European Medicines Agency. 23 October 2008. p. 9. Retrieved 1 September 2016.
  2. 1 2 "Zolinza (vorinostat) Capsules. Full Prescribing Information" (PDF). Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Retrieved 1 September 2016.
  3. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 56" (PDF). WHO Drug Information. 20 (3): 232. 2006. Retrieved 1 September 2016.
  4. ↑ "ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration" (Press release). Merck & Co. June 7, 2006. Retrieved 2006-10-06.
  5. ↑ Lee, J.-H.; Mahendran, A.; Yao, Y.; Ngo, L.; Venta-Perez, G.; Choy, M. L.; Kim, N.; Ham, W.-S.; Breslow, R.; Marks, P. A. (2013). "Development of a histone deacetylase 6 inhibitor and its biological effects". Proceedings of the National Academy of Sciences. 110 (39): 15704–9. Bibcode:2013PNAS..11015704L. PMC 3785767 Freely accessible. PMID 24023063. doi:10.1073/pnas.1313893110.
  6. ↑ Marks, Paul A; Breslow, Ronald (2007). "Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug". Nature Biotechnology. 25 (1): 84–90. PMID 17211407. doi:10.1038/nbt1272.
  7. ↑ HDAC Inhibitors Base (vorinostat)
  8. ↑ "Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 16 February 2014.
  9. ↑ Schaefer, E. W.; Loaiza-Bonilla, A.; Juckett, M.; DiPersio, J. F.; Roy, V.; Slack, J.; Wu, W.; Laumann, K.; Espinoza-Delgado, I.; Gore, S. D. (2009). "A phase 2 study of vorinostat in acute myeloid leukemia". Haematologica. 94 (10): 1375–82. PMC 2754953 Freely accessible. PMID 19794082. doi:10.3324/haematol.2009.009217.
  10. 1 2 Richon, V M (2006). "Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor". British Journal of Cancer. 95 (Suppl 1): S2–S6. PMC 2360770 Freely accessible. doi:10.1038/sj.bjc.6603463.
  11. ↑ Cuneo A, Castoldi. "Mycosis fungoides/Sezary's syndrome". Retrieved 2008-02-15.
  12. ↑ "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. Retrieved 2007-06-03.
  13. ↑ Ramalingam, S. S.; Maitland, M. L.; Frankel, P.; Argiris, A. E.; Koczywas, M.; Gitlitz, B.; Thomas, S.; Espinoza-Delgado, I.; Vokes, E. E.; Gandara, D. R.; Belani, C. P. (2010). "Carboplatin and Paclitaxel in Combination With Either Vorinostat or Placebo for First-Line Therapy of Advanced Non-Small-Cell Lung Cancer". Journal of Clinical Oncology. 28 (1): 56–62. PMC 2799233 Freely accessible. PMID 19933908. doi:10.1200/JCO.2009.24.9094.
  14. ↑ "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)".
  15. ↑ Clinical trial number NCT01319383 for "The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART" at ClinicalTrials.gov
  16. ↑ Archin, Nancie M.; Espeseth, Amy; Parker, Daniel; Cheema, Manzoor; Hazuda, Daria; Margolis, David M. (2009). "Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid". AIDS Research and Human Retroviruses. 25 (2): 207–12. PMC 2853863 Freely accessible. PMID 19239360. doi:10.1089/aid.2008.0191.
  17. ↑ Contreras, X.; Schweneker, M.; Chen, C.-S.; McCune, J. M.; Deeks, S. G.; Martin, J.; Peterlin, B. M. (2009). "Suberoylanilide Hydroxamic Acid Reactivates HIV from Latently Infected Cells". Journal of Biological Chemistry. 284 (11): 6782–9. PMC 2652322 Freely accessible. PMID 19136668. doi:10.1074/jbc.M807898200.
  18. ↑ Bouchecareilh, M.; Hutt, D. M.; Szajner, P.; Flotte, T. R.; Balch, W. E. (2012). "Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of 1-Antitrypsin Deficiency". Journal of Biological Chemistry. 287 (45): 38265–78. PMC 3488095 Freely accessible. PMID 22995909. doi:10.1074/jbc.M112.404707.
  19. ↑ Hutt, Darren M; Herman, David; Rodrigues, Ana P C; Noel, Sabrina; Pilewski, Joseph M; Matteson, Jeanne; Hoch, Ben; Kellner, Wendy; Kelly, Jeffery W; Schmidt, Andre; Thomas, Philip J; Matsumura, Yoshihiro; Skach, William R; Gentzsch, Martina; Riordan, John R; Sorscher, Eric J; Okiyoneda, Tsukasa; Yates, John R; Lukacs, Gergely L; Frizzell, Raymond A; Manning, Gerard; Gottesfeld, Joel M; Balch, William E (2010). "Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis". Nature Chemical Biology. 6 (1): 25–33. PMC 2901172 Freely accessible. PMID 19966789. doi:10.1038/nchembio.275.
  20. ↑ Alam, M. S.; Getz, M.; Haldar, K. (2016). "Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model". Science Translational Medicine. 8 (326): 326ra23. PMID 26888431. doi:10.1126/scitranslmed.aad9407.
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