Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities

Mohammad Alyamani, Zhenfei Li, Michael Berk, Jianneng Li, Jingjie Tang, Sunil Upadhyay, Richard J. Auchus, Nima Sharifi

Research output: Contribution to journalArticle

10 Citations (Scopus)

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. Alyamani et al. show that galeterone, a steroidal androgen signaling inhibitor, is converted by enzymes that normally process endogenous steroids to metabolites that have varying activities on androgen signaling pathway components.

Original languageEnglish (US)
JournalCell Chemical Biology
DOIs
StateAccepted/In press - Jan 22 2017

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Metabolism
Steroids
Androgen Receptors
3-Hydroxysteroid Dehydrogenases
Androgens
Metabolites
Hydroxyl Radical
Oxidoreductases
Androgen Receptor Antagonists
3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
Pregnenolone
Phase III Clinical Trials
Dehydroepiandrosterone
Protein Stability
Castration
Enzymes
Heterografts
Gene expression
Prostatic Neoplasms
Cholesterol

Keywords

  • 3βHSD
  • Abiraterone
  • Androgens
  • CYP17A1
  • Galeterone
  • Metabolism
  • Prostate cancer
  • Steroids

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Drug Discovery
  • Pharmacology

Cite this

Alyamani, M., Li, Z., Berk, M., Li, J., Tang, J., Upadhyay, S., ... Sharifi, N. (Accepted/In press). Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities. Cell Chemical Biology. https://doi.org/10.1016/j.chembiol.2017.05.020

Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities. / Alyamani, Mohammad; Li, Zhenfei; Berk, Michael; Li, Jianneng; Tang, Jingjie; Upadhyay, Sunil; Auchus, Richard J.; Sharifi, Nima.

In: Cell Chemical Biology, 22.01.2017.

Research output: Contribution to journalArticle

Alyamani, Mohammad ; Li, Zhenfei ; Berk, Michael ; Li, Jianneng ; Tang, Jingjie ; Upadhyay, Sunil ; Auchus, Richard J. ; Sharifi, Nima. / Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities. In: Cell Chemical Biology. 2017.
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