Galeterone

{{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

| 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 which was under development by Tokai Pharmaceuticals for the treatment of prostate cancer.<ref name="AdisInsight">{{Cite web|url=http://adisinsight.springer.com/drugs/800031243|title = Galeterone - Eledon Pharmaceuticals | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> It possesses a unique triple mechanism of action, acting as an androgen receptor antagonist, androgen receptor down regulator,<ref>{{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 }}</ref> and CYP17A1 inhibitor,<ref>{{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 }}</ref> the latter of which prevents the biosynthesis of androgens.<ref name="pmid19145273">{{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 }}</ref> As a CYP17A1 inhibitor, galeterone shows selectivity for 17,20-lyase over 17α-hydroxylase.<ref name="pmid24276076">{{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 }}</ref>

Prostate cancer drug 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.<ref name="pmid28648378">{{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 }}</ref> 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, has been identified as an inhibitor of sulfotransferases (SULT2A1, SULT2B1b, SULT1E1), which are involved in the sulfation of dehydroepiandrosterone and other steroids and compounds, with K<sub>i</sub> values in the sub-micromolar range.<ref name="pmid29436390">{{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 }}</ref>

== Clinical development ==

Galeterone was being compared to enzalutamide in a phase III clinical trial (ARMOR3-SV) for AR-V7-expressing metastatic castration-resistant prostate cancer.<ref>{{ClinicalTrialsGov|NCT02438007|A Study of Galeterone Compared to Enzalutamide In Men Expressing Androgen Receptor Splice Variant-7 mRNA (AR-V7) Metastatic CRPC}}</ref><ref name=Silberstein2016>{{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 }}</ref> 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.<ref>{{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}}</ref> On August 22, 2016, the company announced the discontinuation of their phase II expansion (ARMOR2) as well.<ref>{{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 }}</ref>

In August 2017, Tokai Pharmaceuticals discontinued the development of galeterone.<ref name="AdisInsight" /> On December 17, 2018, it was announced that Educational & Scientific, LLC (ESL), in conjunction with University of Maryland ventures, would develop the drug.<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref>

== References == {{Reflist}}

Category:Abandoned drugs Category:Sterols Category:Androstanes Category:Benzimidazoles Category:CYP17A1 inhibitors Category:Steroid sulfotransferase inhibitors Category:Steroidal antiandrogens