@article{d2aec9c8b109424e8aac1c6851e39b9d,
title = "Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities",
abstract = "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 (Δ5,3β-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 3β-hydroxysteroid dehydrogenase (3βHSD). We found that galeterone is metabolized by 3βHSD to Δ4-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3β-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5β-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 Δ5,3β-hydroxyl structure.",
keywords = "3βHSD, CYP17A1, abiraterone, androgens, galeterone, metabolism, prostate cancer, steroids",
author = "Mohammad Alyamani and Zhenfei Li and Michael Berk and Jianneng Li and Jingjie Tang and Sunil Upadhyay and Auchus, {Richard J.} and Nima Sharifi",
note = "Funding Information: We thank Trevor Penning (University of Pennsylvania) for the AKR1C2 construct and David Russell (University of Texas Southwestern Medical Center) for LY191704. We also thank Dave Schumick for the graphical abstract illustration. This work has been supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), a Prostate Cancer Foundation Challenge Award (to N.S.), an American Cancer Society Research Scholar Award ( 12-038-01-CCE ; to N.S.), grants from the National Cancer Institute ( R01CA168899 , R01CA172382 , and R01CA190289 ; to N.S.), a grant from the U.S. Army Medical Research and Materiel Command ( PC121382 to Z.L.), and a Prostate Cancer Foundation Young Investigator Award (to Z.L.). Funding Information: We thank Trevor Penning (University of Pennsylvania) for the AKR1C2 construct and David Russell (University of Texas Southwestern Medical Center) for LY191704. We also thank Dave Schumick for the graphical abstract illustration. This work has been supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), a Prostate Cancer Foundation Challenge Award (to N.S.), an American Cancer Society Research Scholar Award (12-038-01-CCE; to N.S.), grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289; to N.S.), a grant from the U.S. Army Medical Research and Materiel Command (PC121382 to Z.L.), and a Prostate Cancer Foundation Young Investigator Award (to Z.L.). Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",
year = "2017",
month = jul,
day = "20",
doi = "10.1016/j.chembiol.2017.05.020",
language = "English (US)",
volume = "24",
pages = "825--832.e6",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "7",
}