ECEESPE2025 Rapid Communications Rapid Communications 16: Reproductive and Developmental Endocrinology Part 2 (6 abstracts)
Steroidogenesis and CYP17A1 inhibition: development of potent inhibitors for adrenal and gonadal steroid biosynthesis
Jibira Yakubu 1 , Tomasz M. Wróbel 2 , Angelika Grudzińska 2 , Therina du Toit 1 , Katyayani Sharma 1 , Jeremiah C. Harrington 3 , Natalia Dycha 2 , Fredrik Björkling 3 , Flemming Jørgensen 3 & Amit Pandey 1
1University of Bern, Department of Biomedical Research, Bern, Switzerland; 2Medical University of Lublin, Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Lublin, Poland; 3University of Copenhagen, Department of Drug Design and Pharmacology, Copenhagen, Denmark
JOINT384
Steroidogenesis, the biosynthesis of steroid hormones, is a critical process in the development and regulation of various physiological functions, including growth, metabolism, and reproductive health. One of the key enzymes involved in this process is CYP17A1, which catalyses two essential steps in the production of androgens. Given its role in both adrenal and gonadal steroid hormone production, CYP17A1 is a key target for disrupting abnormal steroidogenesis. Only approved CYP17A1 inhibitor is abiraterone, which has numerous side effects, including inhibition of CYP21A2, and is metabolized into a potent androgen, which renders the treatment futile in long term. In this study, we focused on the development of novel potent inhibitors of CYP17A1 to modulate steroid biosynthesis. Using a previously identified hit compound as a starting point, we synthesized a series of analogs, including a novel di-cyano derivative, which demonstrated enhanced potency against CYP17A1. These compounds were tested in the human adrenal NCI-H295R cell line, a well-established model for studying steroidogenesis. Biological assays confirmed that these compounds significantly inhibited CYP17A1 enzymatic activity, leading to changes in steroid hormone profiles. Among the compounds tested, compound 11 exhibited the highest potency (IC50=4 nM) in inhibiting CYP17A1 activity, showing a strong disruption of both hydroxylase and lyase functions of the CYP17A1 enzyme. Compound 14 also showed considerable potency and emerged as a promising lead for further development. Structure-activity relationship (SAR) analysis revealed that compounds containing an indole moiety (e.g., compound 11) were more potent than those with a benzotriazole fragment, suggesting that the indole structure is more effective for CYP17A1 inhibition. These findings indicate that targeting CYP17A1 can be a powerful strategy for modulating steroidogenesis. The compounds developed in this study offer a potential avenue for therapeutic interventions aimed at regulating steroid hormone production in both adrenal and gonadal contexts. Elevated androgen levels in congenital adrenal hyperplasia can be targeted by these potent inhibitors of CYP17A1 and for treatment of hyperandrogenic conditions like polycystic ovary syndrome.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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