Chemical compound
Galeterone Other names TOK-001; VN/124-1; 17-(1H -Benzimidazol-1-yl)androsta-5,16-dien-3β-ol Routes of administration By mouth
(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
CAS Number PubChem CID ChemSpider UNII KEGG CompTox Dashboard (EPA ) ECHA InfoCard 100.233.599 Formula C 26 H 32 N 2 O Molar mass 388.555 g·mol−1 3D model (JSmol )
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
InChI=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
Key: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 .[ 1] It possesses a unique triple mechanism of action , acting as an androgen receptor antagonist , androgen receptor down regulator,[ 2] and CYP17A1 inhibitor ,[ 3] the latter of which prevents the biosynthesis of androgens .[ 4] As a CYP17A1 inhibitor, galeterone shows selectivity for 17,20-lyase over 17α-hydroxylase .[ 5]
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.[ 6] 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 Ki values in the sub-micromolar range.[ 7]
^ "Galeterone - Eledon Pharmaceuticals" . AdisInsight . Springer Nature Switzerland AG.
^ Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK, et al. (August 2008). "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" . Molecular Cancer Therapeutics . 7 (8): 2348–2357. doi :10.1158/1535-7163.MCT-08-0230 . PMC 2643345 . PMID 18723482 .
^ Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, et al. (April 2005). "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 of Medicinal Chemistry . 48 (8): 2972–2984. doi :10.1021/jm040202w . PMID 15828836 .
^ Brawer MK (2008). "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" . Reviews in Urology . 10 (4): 294–296. PMC 2615106 . PMID 19145273 .
^ Yin L, Hu Q (January 2014). "CYP17 inhibitors--abiraterone, C17,20-lyase inhibitors and multi-targeting agents". Nature Reviews. Urology . 11 (1): 32–42. doi :10.1038/nrurol.2013.274 . PMID 24276076 . S2CID 7131777 .
^ Alyamani M, Li Z, Berk M, Li J, Tang J, Upadhyay S, Auchus RJ, Sharifi N (July 2017). "Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities" . Cell Chemical Biology . 24 (7): 825–832.e6. doi :10.1016/j.chembiol.2017.05.020 . PMC 5533090 . PMID 28648378 .
^ Yip CK, Bansal S, Wong SY, Lau AJ (April 2018). "Identification of Galeterone and Abiraterone as Inhibitors of Dehydroepiandrosterone Sulfonation Catalyzed by Human Hepatic Cytosol, SULT2A1, SULT2B1b, and SULT1E1" . Drug Metabolism and Disposition . 46 (4): 470–482. doi :10.1124/dmd.117.078980 . PMID 29436390 .