Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Vorinostat: Difference between pages

{{Short description|Inhibit histone deacetylases (HDAC).}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 470631860

| IUPAC_name = ''N''-Hydroxy-''N'''-phenyloctanediamide

| width = 275

| pronounce = {{IPAc-en|v|ɒ|ˈ|r|ɪ|n|oʊ|s|t|æ|t}} {{respell|vorr|IN|oh-stat}}

| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_status = Rx-only

| routes_of_administration = Oral ([[Capsule (pharmacy)|capsules]])

| bioavailability = 1.8–11%<ref>{{cite web|title=Withdrawal Assessment Report for Vorinostat MSD 100 mg Hard Capsules (vorinostat)|url=http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/01/WC500063049.pdf|publisher=European Medicines Agency|access-date=1 September 2016|page=9|date=23 October 2008}}</ref>

| protein_bound = ~71%

| metabolism = [[Liver|Hepatic]] [[glucuronidation]] and [[Beta oxidation|β-oxidation]]<br>[[Cytochrome P450 oxidase|CYP]] system not involved

| metabolites = vorinostat ''O''-glucuronide, 4-anilino-4-oxobutanoic acid (both inactive)<ref name="Zolinza PI">{{cite web|title=Zolinza (vorinostat) Capsules. Full Prescribing Information|url=https://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_pi.pdf|publisher=Merck & Co., Inc., Whitehouse Station, NJ 08889, USA|access-date=1 September 2016}}</ref>

| elimination_half-life = ~2 hours (vorinostat and ''O''-glucuronide), 11 hours (4-anilino-4-oxobutanoic acid)

| IUPHAR_ligand = 6852

| CAS_number_Ref = {{cascite|correct|CAS}}

| ATC_suffix = XH01

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 45716

'''Vorinostat''' ([[International Nonproprietary Name|rINN]]),<ref>{{cite journal|title=International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 56|journal=WHO Drug Information|date=2006|volume=20|issue=3|page=232|url=http://apps.who.int/medicinedocs/documents/s14181e/s14181e.pdf|archive-url=https://web.archive.org/web/20110705092935/http://apps.who.int/medicinedocs/documents/s14181e/s14181e.pdf|url-status=dead|archive-date=July 5, 2011|access-date=1 September 2016}}</ref> also known as '''suberoylanilide hydroxamic acid''' ([[suberic acid|suberoyl]]+[[aniline|anilide]]+[[hydroxamic acid]] abbreviated as '''SAHA'''), is a member of a larger class of compounds that inhibit [[histone deacetylase]]s (HDAC). [[Histone deacetylase inhibitor]]s (HDI) have a broad spectrum of [[epigenetic]] activities.

Vorinostat is marketed under the name '''Zolinza''' ({{IPAc-en|z|oʊ|ˈ|l|ɪ|n|z|ə}} {{respell|zoh|LIN|zə}}) by [[Merck & Co.|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.<ref name="Zolinza PI" /><ref>{{cite press release | title = ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration | publisher = Merck & Co. | date = June 7, 2006 | url = http://www.merck.com/newsroom/press_releases/research_and_development/2006_0607.html | access-date = 2006-10-06 | archive-url = https://web.archive.org/web/20060914014021/http://www.merck.com/newsroom/press_releases/research_and_development/2006_0607.html | archive-date = September 14, 2006 | url-status = dead | df = mdy-all }}</ref> The compound was developed by Columbia University chemist [[Ronald Breslow]] and Memorial Sloan-Kettering researcher [[Paul Marks (scientist)|Paul Marks]].<ref>{{cite journal | vauthors = Lee JH, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy ML, Kim N, Ham WS, Breslow R, Marks PA | display-authors = 6 | title = Development of a histone deacetylase 6 inhibitor and its biological effects | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 39 | pages = 15704–15709 | date = September 2013 | pmid = 24023063 | pmc = 3785767 | doi = 10.1073/pnas.1313893110 | doi-access = free | bibcode = 2013PNAS..11015704L }}</ref><ref name=":0">{{cite journal | vauthors = Marks PA, Breslow R | title = Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug | journal = Nature Biotechnology | volume = 25 | issue = 1 | pages = 84–90 | date = January 2007 | pmid = 17211407 | doi = 10.1038/nbt1272 | s2cid = 12656582 }}</ref>

==Medical uses==

Vorinostat was the first [[histone deacetylase inhibitor]]<ref>{{cite web | url = http://www.hdacis.com/zolinza.html | work = HDAC Inhibitors Base | title = Vorinostat }}</ref> approved by the U.S. [[Food and Drug Administration]] (FDA) for the treatment of [[Cutaneous T-cell lymphoma|CTCL]] on October 6, 2006.<ref name = MSR>{{cite web|title=Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=16 February 2014|url=http://reference.medscape.com/drug/zolinza-vorinostat-342102}}</ref>

== Development ==

In 1966, [[Charlotte Friend]] published her observation that a suspension of murine [[Acute erythroid leukemia|erythroleukemia]] cells underwent cytodifferentiation to normal erythrocytes when treated with [[Dimethyl sulfoxide|dimethylsulfoxide]] (DMSO, a common drug solvent and [[cryoprotectant]] frequently used for [[cell culture]] freezing) at 280 mmolar.<ref>{{cite journal | vauthors = Friend C, Patuleia MC, De Harven E | title = Erythrocytic maturation in vitro of murine (Friend) virus-induced leukemic cells | journal = National Cancer Institute Monograph | volume = 22 | pages = 505–522 | date = September 1966 | pmid = 5923328 | url = https://pubmed.ncbi.nlm.nih.gov/5923328/ }}</ref><ref>{{cite journal | vauthors = Friend C, Scher W, Holland JG, Sato T | title = Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 2 | pages = 378–382 | date = February 1971 | pmid = 5277089 | pmc = 388942 | doi = 10.1073/pnas.68.2.378 | doi-access = free | bibcode = 1971PNAS...68..378F }}</ref> Memorial Sloan-Kettering researcher [[Paul Marks (scientist)|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.<ref name=":0" /><ref>{{cite book | vauthors = Breslow R | chapter = From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design |date=2016-12-02 | chapter-url = https://onlinelibrary.wiley.com/doi/10.1002/9783527800315.ch1 | title = Successful Drug Discovery |pages=1–11 | veditors = Fischer J, Childers WE |place=Weinheim, Germany |publisher=Wiley-VCH Verlag GmbH & Co. KGaA |language=en |doi=10.1002/9783527800315.ch1 |isbn=978-3-527-80031-5 |access-date=2022-11-18 }}</ref>

== Mechanism of action ==

Vorinostat has been shown to bind to the active site of [[histone deacetylase]]s and act as a chelator for zinc ions also found in the active site of histone deacetylases.<ref name="Richon">{{cite journal | vauthors = Marks PA, Dokmanovic M | title = Histone deacetylase inhibitors: discovery and development as anticancer agents | journal = Expert Opinion on Investigational Drugs | volume = 14 | issue = 12 | pages = 1497–1511 | date = December 2005 | pmid = 16307490 | pmc = 2360770 | doi = 10.1038/sj.bjc.6603463 }}</ref>

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.<ref name="Richon" /> It acts on class I, II and IV of histone deacetylase.

==Clinical trials==

Vorinostat has also been used to treat [[Sézary syndrome]], another type of lymphoma closely related to CTCL.<ref name="atlas">{{cite web | vauthors = Castoldi G, Cuneo A | date = May 2005 | title = Mycosis fungoides/Sezary's syndrome | url=http://atlasgeneticsoncology.org/Anomalies/MycosFungID2039.html | access-date = 2008-02-15 | work = Atlas of Genetics and Cytogenetics in Oncology and Haematology }}</ref>

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).<ref>{{cite press release | title = Vorinostat shows anti-cancer activity in recurrent gliomas | publisher = Mayo Clinic | date = June 3, 2007 | url = http://www.eurekalert.org/pub_releases/2007-06/mc-vsa053007.php | access-date = 2007-06-03 }}</ref> 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.<ref>{{cite journal | vauthors = Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, Thomas S, Espinoza-Delgado I, Vokes EE, Gandara DR, Belani CP | display-authors = 6 | title = Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer | journal = Journal of Clinical Oncology | volume = 28 | issue = 1 | pages = 56–62 | date = January 2010 | pmid = 19933908 | pmc = 2799233 | doi = 10.1200/JCO.2009.24.9094 }}</ref>

It has given encouraging results in a phase II trial<ref>{{cite journal | vauthors = Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM | display-authors = 6 | title = Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome | journal = Journal of Clinical Oncology | volume = 30 | issue = 18 | pages = 2204–2210 | date = June 2012 | pmid = 22585696 | pmc = 4879705 | doi = 10.1200/JCO.2011.38.3265 }}</ref> for [[myelodysplastic syndrome]]s in combination with [[idarubicin]] and [[cytarabine]].<ref>{{cite web | vauthors = Langholtz J, Haehle M | date = 11 January 2012 | work = The MDS Beacon | url = http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/ |title=Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011) |access-date=2012-01-17 |archive-date=2014-10-30 |archive-url=https://web.archive.org/web/20141030050144/http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/ |url-status=dead }}</ref>

It failed to demonstrate efficacy in treating [[acute myeloid leukemia]] in an earlier phase II study.<ref>{{cite journal | vauthors = Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J, Wu W, Laumann K, Espinoza-Delgado I, Gore SD | display-authors = 6 | title = A phase 2 study of vorinostat in acute myeloid leukemia | journal = Haematologica | volume = 94 | issue = 10 | pages = 1375–1382 | date = October 2009 | pmid = 19794082 | pmc = 2754953 | doi = 10.3324/haematol.2009.009217 }}</ref>

==Preclinical investigations==

Vorinostat is being investigated as a potential [[HIV]] latency reversing agent (LRA) as part of an investigational therapeutic strategy known as "shock and kill".<ref>{{ClinicalTrialsGov|NCT01319383|The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART}}</ref> Vorinostat was shown to reactivate HIV in latently HIV-infected [[T cell]]s, both ''in vitro'' and ''in vivo.''<ref name="pmid19239360">{{cite journal | vauthors = Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM | title = Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid | journal = AIDS Research and Human Retroviruses | volume = 25 | issue = 2 | pages = 207–212 | date = February 2009 | pmid = 19239360 | pmc = 2853863 | doi = 10.1089/aid.2008.0191 }}</ref><ref name="pmid19136668">{{cite journal | vauthors = Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, Peterlin BM | title = Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells | journal = The Journal of Biological Chemistry | volume = 284 | issue = 11 | pages = 6782–6789 | date = March 2009 | pmid = 19136668 | pmc = 2652322 | doi = 10.1074/jbc.M807898200 | doi-access = free }}</ref>

Vorinostat also has shown some activity against the pathophysiological changes in [[Alpha 1-antitrypsin deficiency|α₁-antitrypsin deficiency]]<ref>{{cite journal | vauthors = Bouchecareilh M, Hutt DM, Szajner P, Flotte TR, Balch WE | title = Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency | journal = The Journal of Biological Chemistry | volume = 287 | issue = 45 | pages = 38265–38278 | date = November 2012 | pmid = 22995909 | pmc = 3488095 | doi = 10.1074/jbc.M112.404707 | doi-access = free }}</ref> and [[cystic fibrosis]].<ref>{{cite journal | vauthors = Hutt DM, Herman D, Rodrigues AP, Noel S, Pilewski JM, Matteson J, Hoch B, Kellner W, Kelly JW, Schmidt A, Thomas PJ, Matsumura Y, Skach WR, Gentzsch M, Riordan JR, Sorscher EJ, Okiyoneda T, Yates JR, Lukacs GL, Frizzell RA, Manning G, Gottesfeld JM, Balch WE | display-authors = 6 | title = Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis | journal = Nature Chemical Biology | volume = 6 | issue = 1 | pages = 25–33 | date = January 2010 | pmid = 19966789 | pmc = 2901172 | doi = 10.1038/nchembio.275 }}</ref>

Recent evidence also suggests vorinostat can be a therapeutic tool for [[Niemann–Pick disease, type C|Niemann-Pick type C1]] (NPC1), a rare lysosomal lipid storage disease.<ref>{{cite journal | vauthors = Alam MS, Getz M, Haldar K | title = Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model | journal = Science Translational Medicine | volume = 8 | issue = 326 | pages = 326ra23 | date = February 2016 | pmid = 26888431 | doi = 10.1126/scitranslmed.aad9407 | s2cid = 5762569 }}</ref>

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 infection|human papillomavirus]], or HPV.<ref name="HPV">{{cite web | title = Cancer drug may help treat human papillomavirus infections | url=https://www.sciencedaily.com/releases/2018/11/181130153838.htm | work = ScienceDaily | date = 30 November 2018 | access-date = 2018-11-30 }}</ref>

== See also ==

* [[Trichostatin A]]

== References ==

{{Reflist|2}}

== External links ==

* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=SHH Vorinostat bound to proteins] in the [[Protein Data Bank|PDB]]

{{Merck&Co}}

{{Chemotherapeutic agents}}

{{HDAC inhibitors}}

[[Category:Anilides]]

[[Category:Antineoplastic drugs]]

[[Category:Histone deacetylase inhibitors]]

[[Category:Drugs developed by Merck & Co.]]

[[Category:Hydroxamic acids]]

[[Category:Orphan drugs]]