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<p>Estrogen receptor beta (ERβ) is a favorable therapeutic target for mediating inflammation, attenuating fibrosis, and treating cancer. However, selectively targeting ERβ over estrogen receptor alpha (ERα) has been a longstanding challenge. Recently, we developed OSU-ERβ-12, a novel carborane-based ERβ agonist that has a greater than 100-fold selectivity for ERβ over ERα. In this study, we compare the pharmacokinetics and functional activity of OSU-ERβ-12 against the clinical comparator ERβ agonist erteberel (LY500307) in multiple model systems. Pharmacokinetic profiling revealed OSU-ERβ-12 to have superior pharmacokinetics in pre-clinical models compared to LY500307 while maintaining a similar ERβ selectivity. Additionally, OSU-ERβ-12 displayed high human liver microsome stability and negligible CYP, hERG, and off-target interactions. Overall, OSU-ERβ-12 is a potent, selective, pharmacokinetically superior ERβ agonist that warrants additional study.</p>

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OSU-ERβ-12: a promising pre-clinical candidate selective estrogen receptor beta agonist

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Gregory M. Young,
  • Timothy H. Helms,
  • Samuel K. Kulp,
  • Adeoluwa A. Adeluola,
  • Hanna S. Radomska,
  • Tyler A. Wilson,
  • Reena Shakya,
  • Alyssa Kabat,
  • Gillian Mulcahy,
  • Abigail K. Mayo,
  • Raphael A. Malbrue,
  • William C. Kisseberth,
  • Chad E. Bennett,
  • Christopher C. Coss

摘要

Estrogen receptor beta (ERβ) is a favorable therapeutic target for mediating inflammation, attenuating fibrosis, and treating cancer. However, selectively targeting ERβ over estrogen receptor alpha (ERα) has been a longstanding challenge. Recently, we developed OSU-ERβ-12, a novel carborane-based ERβ agonist that has a greater than 100-fold selectivity for ERβ over ERα. In this study, we compare the pharmacokinetics and functional activity of OSU-ERβ-12 against the clinical comparator ERβ agonist erteberel (LY500307) in multiple model systems. Pharmacokinetic profiling revealed OSU-ERβ-12 to have superior pharmacokinetics in pre-clinical models compared to LY500307 while maintaining a similar ERβ selectivity. Additionally, OSU-ERβ-12 displayed high human liver microsome stability and negligible CYP, hERG, and off-target interactions. Overall, OSU-ERβ-12 is a potent, selective, pharmacokinetically superior ERβ agonist that warrants additional study.