# Galeterone
> Mediated Wiki article. Canonical URL: https://mediated.wiki/source/Galeterone
> Markdown URL: https://mediated.wiki/source/Galeterone.md
> Source: https://en.wikipedia.org/wiki/Galeterone
> Source revision: 1335569389
> License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/)
{{Short description|Chemical compound}}
{{Drugbox
| verifiedrevid =
| IUPAC_name = (3S,8R,9S,10R,13S,14S)-17-(benzimidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol
| image = Galeterone.svg
| image_class = skin-invert-image
| width = 250px
| tradename =
| Drugs.com =
| MedlinePlus =
| pregnancy_AU =
| pregnancy_US =
| legal_AU =
| legal_UK =
| legal_US =
| routes_of_administration = [By mouth](/source/Oral_administration)
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number = 851983-85-2
| ATC_prefix =
| ATC_suffix =
| PubChem = 11188409
| DrugBank =
| ChemSpiderID = 9363493
| KEGG = D10125
| KEGG_Ref = {{keggcite|correct|kegg}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = WA33E149SW
| synonyms = TOK-001; VN/124-1; 17-(1''H''-Benzimidazol-1-yl)androsta-5,16-dien-3β-ol
| C=26 | H=32 | N = 2| O=1
| SMILES = C[C@]12CC[C@@H](CC1=CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC=C4N5C=NC6=CC=CC=C65)C)O
| StdInChI = 1S/C26H32N2O/c1-25-13-11-18(29)15-17(25)7-8-19-20-9-10-24(26(20,2)14-12-21(19)25)28-16-27-22-5-3-4-6-23(22)28/h3-7,10,16,18-21,29H,8-9,11-15H2,1-2H3/t18-,19-,20-,21-,25-,26-/m0/s1
| StdInChIKey = PAFKTGFSEFKSQG-PAASFTFBSA-N
}}
'''Galeterone''' (developmental code names '''TOK-001''', '''VN/124-1''') is a [steroidal antiandrogen](/source/steroidal_antiandrogen) which was under development by Tokai Pharmaceuticals for the treatment of [prostate cancer](/source/prostate_cancer).[{{Cite web|url=http://adisinsight.springer.com/drugs/800031243|title = Galeterone - Eledon Pharmaceuticals | work = AdisInsight | publisher = Springer Nature Switzerland AG }}] It possesses a unique triple [mechanism of action](/source/mechanism_of_action), acting as an [androgen receptor](/source/androgen_receptor) [antagonist](/source/receptor_antagonist), androgen receptor down regulator,[{{cite journal | vauthors = Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK, Guo Z, Fang HB, Njar VC, Brodie AM | display-authors = 6 | title = Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer | journal = Molecular Cancer Therapeutics | volume = 7 | issue = 8 | pages = 2348–2357 | date = August 2008 | pmid = 18723482 | pmc = 2643345 | doi = 10.1158/1535-7163.MCT-08-0230 }}] and [CYP17A1 inhibitor](/source/CYP17A1_inhibitor),[{{cite journal | vauthors = Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D, Farquhar R, Guo Z, Qiu Y, Brodie AM | display-authors = 6 | title = Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 8 | pages = 2972–2984 | date = April 2005 | pmid = 15828836 | doi = 10.1021/jm040202w }}] the latter of which prevents the [biosynthesis](/source/biosynthesis) of [androgen](/source/androgen)s.[{{cite journal | vauthors = Brawer MK | title = New treatments for castration-resistant prostate cancer: highlights from the 44th annual meeting of the american society of clinical oncology, may 30-june 3, 2008, chicago, IL | journal = Reviews in Urology | volume = 10 | issue = 4 | pages = 294–296 | year = 2008 | pmid = 19145273 | pmc = 2615106 }}] As a CYP17A1 inhibitor, galeterone shows selectivity for [17,20-lyase](/source/17%2C20-lyase) over [17α-hydroxylase](/source/17%CE%B1-hydroxylase).[{{cite journal | vauthors = Yin L, Hu Q | title = CYP17 inhibitors--abiraterone, C17,20-lyase inhibitors and multi-targeting agents | journal = Nature Reviews. Urology | volume = 11 | issue = 1 | pages = 32–42 | date = January 2014 | pmid = 24276076 | doi = 10.1038/nrurol.2013.274 | s2cid = 7131777 }}]
Prostate cancer drug [abiraterone](/source/abiraterone) and its analog galeterone are Δ5,3β-hydroxy steroids. Structures of these two agents are identical to endogenous steroid substrates (cholesterole, dehydroepiandorosterone and pregnenolone) for the 3β-hydroxysteroid dehydrogenase (3βHSD) of endocrine system. It has been reported that both of these agents are metabolized to 3-oxo-Δ4-steroids by 3βHSD in short period on oral administration. First metabolite 3-oxo-Δ4-abiraterone has more potent anti-prostate cancer properties than abiraterone where galeterone metabolite (3-oxo-Δ4-galaterone) has activity comparable to parent. Further these two metabolites undergo metabolism by 5α-reductase (5α-SRD) of endocrine system which leads to five more biologically inactive metabolites.[{{cite journal | vauthors = Alyamani M, Li Z, Berk M, Li J, Tang J, Upadhyay S, Auchus RJ, Sharifi N | title = Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities | journal = Cell Chemical Biology | volume = 24 | issue = 7 | pages = 825–832.e6 | date = July 2017 | pmid = 28648378 | pmc = 5533090 | doi = 10.1016/j.chembiol.2017.05.020 }}] It is known that galeterone has poor oral bioavailability in rodents. Poor pharmacokinetic properties (oral absorption and metabolic half-life) of galeterone may be the reason for its clinical compromise.
Galeterone, along with [abiraterone acetate](/source/abiraterone_acetate), has been identified as an inhibitor of [sulfotransferase](/source/sulfotransferase)s ([SULT2A1](/source/SULT2A1), [SULT2B1b](/source/SULT2B1b), [SULT1E1](/source/SULT1E1)), which are involved in the [sulfation](/source/sulfation) of [dehydroepiandrosterone](/source/dehydroepiandrosterone) and other [steroid](/source/steroid)s and compounds, with Ki values in the sub-micromolar range.[{{cite journal | vauthors = Yip CK, Bansal S, Wong SY, Lau AJ | title = Identification of Galeterone and Abiraterone as Inhibitors of Dehydroepiandrosterone Sulfonation Catalyzed by Human Hepatic Cytosol, SULT2A1, SULT2B1b, and SULT1E1 | journal = Drug Metabolism and Disposition | volume = 46 | issue = 4 | pages = 470–482 | date = April 2018 | pmid = 29436390 | doi = 10.1124/dmd.117.078980 | doi-access = free }}]
== Clinical development ==
Galeterone was being compared to [enzalutamide](/source/enzalutamide) in a [phase III](/source/Phase_III_clinical_trials) [clinical trial](/source/clinical_trial) (ARMOR3-SV) for [AR-V7](/source/AR-V7)-expressing metastatic [castration-resistant prostate cancer](/source/castration-resistant_prostate_cancer).[{{ClinicalTrialsGov|NCT02438007|A Study of Galeterone Compared to Enzalutamide In Men Expressing Androgen Receptor Splice Variant-7 mRNA (AR-V7) Metastatic CRPC}}][{{cite journal | vauthors = Silberstein JL, Taylor MN, Antonarakis ES | title = Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer | journal = Current Urology Reports | volume = 17 | issue = 4 | article-number = 29 | date = April 2016 | pmid = 26902623 | pmc = 4888068 | doi = 10.1007/s11934-016-0584-4 }}] Tokai announced the discontinuation of ARMOR3-SV on July 26, 2016, after a data monitoring committee determined that the trial was unlikely to meet its endpoint.[{{Cite press release|url=http://www.businesswire.com/news/home/20160726005553/en/Tokai-Pharmaceuticals-Announces-Clinical-Update|title = Tokai Pharmaceuticals Announces Clinical Update|date = 26 July 2016}}] On August 22, 2016, the company announced the discontinuation of their phase II expansion (ARMOR2) as well.[{{Cite web|url=http://seekingalpha.com/news/3204773-tokai-pharma-flux-lead-product-candidate-galeterone-enrollment-mid-stage-prostate-cancer|title = Tokai Pharma in flux with lead product candidate galeterone, enrollment in mid-stage prostate cancer study nixed; shares slump 23% after hours (NASDAQ:ELDN) | work = Seeking Alpha| date=22 August 2016 }}]
In August 2017, Tokai Pharmaceuticals discontinued the development of galeterone.[{{Cite web|url=https://ww.stockgitter.com/USD/news/lowe-inks-new-deal-for-clinical-trials-of-another-cancer-drug|title=Lowe inks new deal for clinical trials of another cancer drug|website=Stock Gitter|access-date=2019-04-03|archive-date=2019-04-03|archive-url=https://web.archive.org/web/20190403225329/https://ww.stockgitter.com/USD/news/lowe-inks-new-deal-for-clinical-trials-of-another-cancer-drug|url-status=dead}}][{{Cite web|url=https://www.biospace.com/article/educational-and-scientific-llc-and-university-of-maryland-baltimore-expand-relationship-through-licensing-agreement-to-develop-novel-prostate-cancer-treatment/|title=Educational & Scientific, LLC and University of Maryland, Baltimore Expand Relationship Through Licensing Agreement to Develop Novel Prostate Cancer Treatment |website=BioSpace|date=17 December 2018 |language=en-US|access-date=2019-04-03}}][{{Cite web|url=https://www.umventures.org/news/jamaica-observer-lowe-and-team-granted-licence-further-development-prostate-cancer-drug|title=Jamaica Observer: Lowe and Team Granted Licence for Further Development of Prostate Cancer Drug|website=www.umventures.org|language=en|access-date=2019-04-03}}]
== References ==
{{Reflist}}
{{Androgens and antiandrogens}}
{{Androgen receptor modulators}}
Category:Abandoned drugs
Category:Sterols
Category:Androstanes
Category:Benzimidazoles
Category:CYP17A1 inhibitors
Category:Steroid sulfotransferase inhibitors
Category:Steroidal antiandrogens
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Adapted from the Wikipedia article [Galeterone](https://en.wikipedia.org/wiki/Galeterone) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Galeterone?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.