PMID- 28648378
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20231112
IS  - 2451-9448 (Electronic)
IS  - 2451-9456 (Print)
IS  - 2451-9448 (Linking)
VI  - 24
IP  - 7
DP  - 2017 Jul 20
TI  - Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical 
      Activities.
PG  - 825-832.e6
LID - S2451-9456(17)30183-6 [pii]
LID - 10.1016/j.chembiol.2017.05.020 [doi]
AB  - Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, 
      and AR degrader, under evaluation in a phase III clinical trial for 
      castration-resistant prostate cancer (CRPC). The A/B steroid ring 
      (Delta(5),3beta-hydroxyl) structure of galeterone is identical to that of cholesterol, 
      which makes endogenous steroids with the same structure (e.g., 
      dehydroepiandrosterone and pregnenolone) substrates for the enzyme 
      3beta-hydroxysteroid dehydrogenase (3betaHSD). We found that galeterone is metabolized 
      by 3betaHSD to Delta(4)-galeterone (D4G), which is further converted by 
      steroid-5alpha-reductase (SRD5A) to 3-keto-5alpha-galeterone (5alphaG), 3alpha-OH-5alpha-galeterone, 
      and 3beta-OH-5alpha-galeterone; in vivo it is also converted to the three corresponding 
      5beta-reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein 
      stability, AR target gene expression, and xenograft growth comparably with 
      galeterone, and further conversion by SRD5A leads to loss of several activities 
      that inhibit the androgen axis that may compromise clinical efficacy. Together, 
      these findings define a critical metabolic class effect of steroidal drugs with a 
      Delta(5),3beta-hydroxyl structure.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Alyamani, Mohammad
AU  - Alyamani M
AD  - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 
      Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, 
      Cleveland, OH 44115, USA.
FAU - Li, Zhenfei
AU  - Li Z
AD  - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 
      Cleveland, OH 44195, USA.
FAU - Berk, Michael
AU  - Berk M
AD  - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 
      Cleveland, OH 44195, USA.
FAU - Li, Jianneng
AU  - Li J
AD  - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 
      Cleveland, OH 44195, USA.
FAU - Tang, Jingjie
AU  - Tang J
AD  - CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular 
      Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese 
      Academy of Sciences, Shanghai 200031, P.R. China.
FAU - Upadhyay, Sunil
AU  - Upadhyay S
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine and 
      Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 
      48103, USA.
FAU - Auchus, Richard J
AU  - Auchus RJ
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine and 
      Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 
      48103, USA.
FAU - Sharifi, Nima
AU  - Sharifi N
AD  - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 
      Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, 
      Cleveland, OH 44115, USA; Department of Urology, Glickman Urological and Kidney 
      Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Hematology 
      and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, 
      USA. Electronic address: sharifn@ccf.org.
LA  - eng
GR  - R01 CA168899/CA/NCI NIH HHS/United States
GR  - R01 CA172382/CA/NCI NIH HHS/United States
GR  - R01 CA190289/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20170622
PL  - United States
TA  - Cell Chem Biol
JT  - Cell chemical biology
JID - 101676030
RN  - 0 (Androstadienes)
RN  - 0 (Benzimidazoles)
RN  - 0 (Receptors, Androgen)
RN  - 73R90F7MQ8 (Pregnenolone)
RN  - EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.- (Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.357 (AKR1C2 protein, human)
RN  - EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase)
RN  - EC 1.14.14.19 (CYP17A1 protein, human)
RN  - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
RN  - EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase)
RN  - WA33E149SW (3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene)
SB  - IM
CIN - Nat Rev Urol. 2017 Oct;14(10):590-592. PMID: 28786422
MH  - 17-Hydroxysteroid Dehydrogenases/genetics/metabolism
MH  - 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics/metabolism
MH  - Androstadienes/analysis/*metabolism/therapeutic use
MH  - Animals
MH  - Benzimidazoles/analysis/*metabolism/therapeutic use
MH  - Cell Line, Tumor
MH  - Chromatography, High Pressure Liquid
MH  - HEK293 Cells
MH  - Humans
MH  - Hydroxysteroid Dehydrogenases/genetics/metabolism
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Mice
MH  - Pregnenolone/pharmacology
MH  - Prostatic Neoplasms/drug therapy/mortality/pathology
MH  - Receptors, Androgen/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Steroid 17-alpha-Hydroxylase/antagonists & inhibitors/metabolism
MH  - Tandem Mass Spectrometry
MH  - Transplantation, Heterologous
PMC - PMC5533090
MID - NIHMS878757
OTO - NOTNLM
OT  - 3betaHSD
OT  - CYP17A1
OT  - abiraterone
OT  - androgens
OT  - galeterone
OT  - metabolism
OT  - prostate cancer
OT  - steroids
EDAT- 2017/06/27 06:00
MHDA- 2017/09/28 06:00
PMCR- 2018/07/20
CRDT- 2017/06/27 06:00
PHST- 2017/01/22 00:00 [received]
PHST- 2017/04/21 00:00 [revised]
PHST- 2017/05/16 00:00 [accepted]
PHST- 2017/06/27 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2017/06/27 06:00 [entrez]
PHST- 2018/07/20 00:00 [pmc-release]
AID - S2451-9456(17)30183-6 [pii]
AID - 10.1016/j.chembiol.2017.05.020 [doi]
PST - ppublish
SO  - Cell Chem Biol. 2017 Jul 20;24(7):825-832.e6. doi: 
      10.1016/j.chembiol.2017.05.020. Epub 2017 Jun 22.