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Vorinostat

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Vorinostat
BERJAYA
Clinical data
Pronunciation/vɒˈrɪnoʊstæt/ vorr-IN-oh-stat
Trade namesZolinza
Other namesSuberoylanilide hydroxamic acid; SAHA; L-001079038; MK-0683; MK0683
AHFS/Drugs.comMonograph
MedlinePlusa607050
License data
Routes of
administration		Oral (capsules)[1]
Drug classHistone deacetylase inhibitor; Antineoplastic agent
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)[2]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability1.8–11%[1]
Protein binding~71%
MetabolismHepatic glucuronidation and β-oxidation
CYP system not involved
Metabolitesvorinostat O-glucuronide, 4-anilino-4-oxobutanoic acid (both inactive)[3]
Elimination half-life~2 hours (vorinostat and O-glucuronide), 11 hours (4-anilino-4-oxobutanoic acid)
ExcretionRenal (negligible)
Identifiers
  • N-Hydroxy-N'-phenyloctanediamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.207.822 Edit this at Wikidata
Chemical and physical data
FormulaC14H20N2O3
Molar mass264.325 g·mol−1
3D model (JSmol)
  • O=C(Nc1ccccc1)CCCCCCC(=O)NO
  • InChI=1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18) checkY
  • Key:WAEXFXRVDQXREF-UHFFFAOYSA-N checkY
 X markNcheckY (what is this?)  (verify)

Vorinostat (INNTooltip International Nonproprietary Name),[4] also known as suberoylanilide hydroxamic 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.[3][5] The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.[6][7]

Medical uses

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Vorinostat was the first histone deacetylase inhibitor[8] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006.[9] It is taken once daily with food.[10]

Available forms

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Vorinostat is available in the form of 100 mg oral capsules.[10]

Pharmacology

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Pharmacodynamics

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Vorinostat activities
EnzymeIC50Tooltip Half-maximal inhibitory concentration (nM)
HDAC11–48
HDAC22–73
HDAC33–21
HDAC4>25,000
HDAC5>15,000
HDAC60.5–100
HDAC7>25,000
HDAC8290–1,410
HDAC9>25,000
HDAC1060
HDAC1131
Refs: [11][12][13][14][15]

Vorinostat has been shown to bind to the active site of histone deacetylases (HDACs) and act as a chelator for zinc ions also found in the active site of histone deacetylases.[16] It specifically inhibits the class I HDAC1, HDAC2, and HDAC3 and the class IIb HDAC6, all with high nanomolar potency.[10][11] 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.[16]

Pharmacokinetics

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Absorption

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The oral bioavailability of vorinostat is 1.8 to 11%.[1] The time to peak levels (Tmax) of vorinostat varies depending on whether it is taken while fasted or with a high-fat meal.[10] Its Tmax while fasted was median 1.5 hours (range 0.5–10 hours), whereas its Tmax with a high-fat meal was median 4 hours (range 2–10 hours).[10] Hence, a high-fat meal delayed its Tmax by about 2.5 hours.[10]

Distribution

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Vorinostat shows poor brain penetrance and only subtle brain HDAC inhibition in rodents.[17][18][19] It is known to be a substrate for the blood–brain barrier efflux transporters P-glycoprotein and breast cancer resistance protein (BCRP).[18] The plasma protein binding of vorinostat is approximately 71%.[10]

Metabolism

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Vorinostat is metabolized by glucuronidation and by hydrolysis followed by β-oxidation.[10] The two major metabolites of vorinostat circulate at 4- to 13-fold higher concentrations than vorinostat itself and are pharmacologically inactive.[10] Vorinostat is not metabolized by cytochrome P450 enzymes.[10]

Elimination

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The elimination half-life of vorinostat is approximately 2 hours.[10]

History

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In 1966, Charlotte Friend published her observation that a suspension of murine erythroleukemia cells underwent cytodifferentiation to normal erythrocytes when treated with dimethylsulfoxide (DMSO, a common drug solvent and cryoprotectant frequently used for cell culture freezing) at 280 mmolar.[20][21] Memorial Sloan-Kettering researcher Paul Marks approached Columbia University chemist Ronald Breslow about these findings and together they decided to develop more potent analogs of DMSO, in order to make use of this property for cancer treatment. Their optimization process lead to the discovery of suberoylanilide hydroxamic acid and its HDAC-inhibiting property.[7][22]

Research

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Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.[23]

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).[24] Further brain tumor trials are planned in which vorinostat will be combined with other drugs. [citation needed]

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.[25]

It has given encouraging results in a phase II trial[26] for myelodysplastic syndromes in combination with idarubicin and cytarabine.[27] It failed to demonstrate efficacy in treating acute myeloid leukemia in an earlier phase II study.[28]

Preclinical research

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Vorinostat is being investigated as a potential HIV latency reversing agent (LRA) as part of an investigational therapeutic strategy known as "shock and kill".[29] Vorinostat was shown to reactivate HIV in latently HIV-infected T cells, both in vitro and in vivo.[30][31]

Vorinostat also has shown some activity against the pathophysiological changes in α1-antitrypsin deficiency[32] and cystic fibrosis.[33] Recent evidence also suggests vorinostat can be a therapeutic tool for Niemann-Pick type C1 (NPC1), a rare lysosomal lipid storage disease.[34]

Preclinical experiments by University of Alabama at Birmingham researchers suggest the cancer drugs vorinostat, belinostat, and panobinostat might be repurposed to treat infections caused by human papillomavirus, or HPV.[35]

See also

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References

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  1. 1 2 3 "Withdrawal Assessment Report for Vorinostat MSD 100 mg Hard Capsules (vorinostat)" (PDF). European Medicines Agency. 23 October 2008. p. 9. Archived from the original (PDF) on 15 September 2016. Retrieved 1 September 2016.
  2. ↑ "Therapeutic Goods (Poisons Standard—February 2026) Instrument 2026". Federal Register of Legislation. February 2026. Retrieved 11 May 2026.
  3. 1 2 "Zolinza (vorinostat) Capsules. Full Prescribing Information" (PDF). Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Retrieved 1 September 2016.
  4. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 56" (PDF). WHO Drug Information. 20 (3): 232. 2006. Archived from the original (PDF) on July 5, 2011. Retrieved 1 September 2016.
  5. ↑ "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. Archived from the original on September 14, 2006. Retrieved October 6, 2006.
  6. ↑ Lee JH, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy ML, et al. (September 2013). "Development of a histone deacetylase 6 inhibitor and its biological effects". Proceedings of the National Academy of Sciences of the United States of America. 110 (39): 15704–15709. Bibcode:2013PNAS..11015704L. doi:10.1073/pnas.1313893110. PMC 3785767. PMID 24023063.
  7. 1 2 Marks PA, Breslow R (January 2007). "Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug". Nature Biotechnology. 25 (1): 84–90. doi:10.1038/nbt1272. PMID 17211407. S2CID 12656582.
  8. ↑ "Vorinostat". HDAC Inhibitors Base.
  9. ↑ "Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 16 February 2014.
  10. 1 2 3 4 5 6 7 8 9 10 11 https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021991s002lbl.pdf
  11. 1 2 Fass DM, Reis SA, Ghosh B, Hennig KM, Joseph NF, Zhao WN, Nieland TJ, Guan JS, Kuhnle CE, Tang W, Barker DD, Mazitschek R, Schreiber SL, Tsai LH, Haggarty SJ (January 2013). "Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity". Neuropharmacology. 64: 81–96. doi:10.1016/j.neuropharm.2012.06.043. PMC 3447535. PMID 22771460.
  12. ↑ Moradei O, Maroun CR, Paquin I, Vaisburg A (September 2005). "Histone deacetylase inhibitors: latest developments, trends and prospects". Curr Med Chem Anticancer Agents. 5 (5): 529–560. doi:10.2174/1568011054866946. PMID 16178777.
  13. ↑ Zagni C, Floresta G, Monciino G, Rescifina A (November 2017). "The Search for Potent, Small-Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat". Med Res Rev. 37 (6): 1373–1428. doi:10.1002/med.21437. PMID 28181261.
  14. ↑ Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G (March 2010). "Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease". Neuropsychopharmacology. 35 (4): 870–880. doi:10.1038/npp.2009.197. PMC 3055373. PMID 20010553.
  15. ↑ Abdallah DI, de Araujo ED, Patel NH, Hasan LS, Moriggl R, Krämer OH, Gunning PT (2023). "Medicinal chemistry advances in targeting class I histone deacetylases". Explor Target Antitumor Ther. 4 (4): 757–779. doi:10.37349/etat.2023.00166. PMC 10497394. PMID 37711592.
  16. 1 2 Marks PA, Dokmanovic M (December 2005). "Histone deacetylase inhibitors: discovery and development as anticancer agents". Expert Opinion on Investigational Drugs. 14 (12): 1497–1511. doi:10.1038/sj.bjc.6603463. PMC 2360770. PMID 16307490.
  17. ↑ Schroeder FA, Wang C, Van de Bittner GC, Neelamegam R, Takakura WR, Karunakaran A, Wey HY, Reis SA, Gale J, Zhang YL, Holson EB, Haggarty SJ, Hooker JM (October 2014). "PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat". ACS Chem Neurosci. 5 (10): 1055–1062. doi:10.1021/cn500162j. PMC 4198064. PMID 25188794. Quantification of dynamic imaging data revealed that the hydroxamates SAHA and givinostat both resulted in only subtle blockade of radiotracer binding in whole brain (Figure 3A), consistent with recent reports demonstrating poor brain penetrance of the prototypical hydroxamic acid HDAC inhibitor, SAHA.14,15
  18. 1 2 Hanson JE, La H, Plise E, Chen YH, Ding X, Hanania T, Sabath EV, Alexandrov V, Brunner D, Leahy E, Steiner P, Liu L, Scearce-Levie K, Zhou Q (2013). "SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition". PLOS ONE. 8 (7) e69964. Bibcode:2013PLoSO...869964H. doi:10.1371/journal.pone.0069964. PMC 3724849. PMID 23922875.
  19. ↑ Wang C, Eessalu TE, Barth VN, Mitch CH, Wagner FF, Hong Y, Neelamegam R, Schroeder FA, Holson EB, Haggarty SJ, Hooker JM (2013). "Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain". Am J Nucl Med Mol Imaging. 4 (1): 29–38. PMC 3867727. PMID 24380043.
  20. ↑ Friend C, Patuleia MC, De Harven E (September 1966). "Erythrocytic maturation in vitro of murine (Friend) virus-induced leukemic cells". National Cancer Institute Monograph. 22: 505–522. PMID 5923328.
  21. ↑ Friend C, Scher W, Holland JG, Sato T (February 1971). "Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide". Proceedings of the National Academy of Sciences of the United States of America. 68 (2): 378–382. Bibcode:1971PNAS...68..378F. doi:10.1073/pnas.68.2.378. PMC 388942. PMID 5277089.
  22. ↑ Breslow R (2016-12-02). "From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design". In Fischer J, Childers WE (eds.). Successful Drug Discovery. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA. pp. 1–11. doi:10.1002/9783527800315.ch1. ISBN 978-3-527-80031-5. Retrieved 2022-11-18.
  23. ↑ Castoldi G, Cuneo A (May 2005). "Mycosis fungoides/Sezary's syndrome". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-02-15.
  24. ↑ "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. Archived from the original on 2007-10-10. Retrieved 2007-06-03.
  25. ↑ Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, et al. (January 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. doi:10.1200/JCO.2009.24.9094. PMC 2799233. PMID 19933908.
  26. ↑ Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, et al. (June 2012). "Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome". Journal of Clinical Oncology. 30 (18): 2204–2210. doi:10.1200/JCO.2011.38.3265. PMC 4879705. PMID 22585696.
  27. ↑ Langholtz J, Haehle M (11 January 2012). "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)". The MDS Beacon. Archived from the original on 2014-10-30. Retrieved 2012-01-17.
  28. ↑ Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J, et al. (October 2009). "A phase 2 study of vorinostat in acute myeloid leukemia". Haematologica. 94 (10): 1375–1382. doi:10.3324/haematol.2009.009217. PMC 2754953. PMID 19794082.
  29. ↑ 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
  30. ↑ Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM (February 2009). "Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid". AIDS Research and Human Retroviruses. 25 (2): 207–212. doi:10.1089/aid.2008.0191. PMC 2853863. PMID 19239360.
  31. ↑ Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, Peterlin BM (March 2009). "Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells". The Journal of Biological Chemistry. 284 (11): 6782–6789. doi:10.1074/jbc.M807898200. PMC 2652322. PMID 19136668.
  32. ↑ Bouchecareilh M, Hutt DM, Szajner P, Flotte TR, Balch WE (November 2012). "Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency". The Journal of Biological Chemistry. 287 (45): 38265–38278. doi:10.1074/jbc.M112.404707. PMC 3488095. PMID 22995909.
  33. ↑ Hutt DM, Herman D, Rodrigues AP, Noel S, Pilewski JM, Matteson J, et al. (January 2010). "Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis". Nature Chemical Biology. 6 (1): 25–33. doi:10.1038/nchembio.275. PMC 2901172. PMID 19966789.
  34. ↑ Alam MS, Getz M, Haldar K (February 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. doi:10.1126/scitranslmed.aad9407. PMID 26888431. S2CID 5762569.
  35. ↑ "Cancer drug may help treat human papillomavirus infections". ScienceDaily. 30 November 2018. Retrieved 2018-11-30.
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