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Published on: August 13, 2019
OSU-ERβ-12: a promising pre-clinical candidate selective estrogen receptor beta agonist
Gregory M Young1, Timothy H Helms1, Samuel K Kulp1
1Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave, Columbus, OH, 43210, USA.
Abstract:
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.
Insights
A new drug, OSU-ERβ-12, shows high selectivity for estrogen receptor beta (ERβ) and better pharmacokinetics than existing treatments. This potent ERβ agonist may offer new therapeutic options for inflammation, fibrosis, and cancer.
Area of Science:
- Pharmacology
- Endocrinology
- Drug Discovery
Background:
- Estrogen receptor beta (ERβ) is a key therapeutic target for inflammatory diseases, fibrosis, and cancers.
- Selective targeting of ERβ over estrogen receptor alpha (ERα) remains a significant challenge in drug development.
Purpose of the Study:
- To compare the pharmacokinetic and functional profiles of a novel ERβ agonist, OSU-ERβ-12, with a clinical comparator, erteberel (LY500307).
- To evaluate the selectivity, stability, and off-target interactions of OSU-ERβ-12.
Main Methods:
- Development of OSU-ERβ-12, a novel carborane-based ERβ agonist with >100-fold selectivity for ERβ over ERα.
- Pharmacokinetic profiling and functional activity assessment in multiple pre-clinical model systems.
- In vitro assays for human liver microsome stability and off-target interactions (CYP, hERG).
Main Results:
- OSU-ERβ-12 demonstrated superior pharmacokinetics in pre-clinical models compared to LY500307.
- OSU-ERβ-12 maintained high ERβ selectivity and exhibited excellent human liver microsome stability.
- Negligible interactions with CYP enzymes and hERG channels were observed for OSU-ERβ-12, indicating a favorable safety profile.
Conclusions:
- OSU-ERβ-12 is a potent and highly selective ERβ agonist with improved pharmacokinetic properties.
- Its favorable safety profile and enhanced efficacy suggest OSU-ERβ-12 warrants further investigation as a therapeutic agent.
