2. Academic Validation
  3. Pyridine indole hybrids as novel potent CYP17A1 inhibitors

Pyridine indole hybrids as novel potent CYP17A1 inhibitors

  • J Enzyme Inhib Med Chem. 2025 Dec;40(1):2463014. doi: 10.1080/14756366.2025.2463014.
Tomasz M Wróbel 1 2,  Angelika Grudzińska 1,  Jibira Yakubu 3 4 5,  Therina du Toit 6,  Katyayani Sharma 3 4,  Jeremiah C Harrington 2,  Fredrik Björkling 2,  Flemming Steen Jørgensen 2,  Amit V Pandey 3 4
Affiliations

Affiliations

  • 1 Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Lublin, Poland.
  • 2 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • 3 Pediatric Endocrinology, Department of Pediatrics, University Children's Hospital, University of Bern, Bern, Switzerland.
  • 4 Translational Hormone Research Program, Department of Biomedical Research, University of Bern, Bern, Switzerland.
  • 5 Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
  • 6 Department of Nephrology and Hypertension, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland.
PMID: 39950830 DOI: 10.1080/14756366.2025.2463014
Abstract

Prostate Cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by drug resistance and adverse effects. This study reports the synthesis and evaluation of novel CYP17A1 inhibitors derived from a previously identified hit compound. Several analogs were synthesised, including an unexpected di-cyano derivative, which demonstrated increased potency against CYP17A1 compared to abiraterone. Biological assays revealed that these compounds significantly inhibited CYP17A1 enzymatic activity and altered steroid biosynthesis. Among the newly synthesised inhibitors, compound 11 showed the highest potency (IC50 = 4 nM) and the related compound 14 presented a template for further development. A combined docking and molecular dynamics approach was used to identify the possible target binding modes of the compounds.

Keywords

CYP17A1; enzyme inhibition; inhibitors; prostate cancer.

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