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Synthesis and Structure-Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer

Tomasz M Wróbel1,2, Oksana Rogova1, Katyayani Sharma3,4

  • 1Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.

Biomolecules
|February 25, 2022
PubMed

Insights

Researchers developed new non-steroidal compounds targeting CYP17A1 for prostate cancer treatment. The most potent compound showed efficacy comparable to abiraterone, offering a promising new therapeutic avenue.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Pharmacology

Background:

  • Prostate cancer is a leading cancer in men, with CYP17A1 inhibition being a key therapeutic strategy.
  • Benzimidazole scaffolds have previously shown potential in developing CYP17A1 inhibitors.

Purpose of the Study:

  • To synthesize and evaluate novel benzimidazole-based compounds targeting CYP17A1 for prostate cancer treatment.
  • To assess the inhibitory activity, selectivity, and antiproliferative effects of these new compounds.

Main Methods:

  • Synthesis of twenty new benzimidazole derivatives.
  • In vitro assays for CYP17A1 hydroxylase and lyase inhibition.
  • Assays for CYP3A4 and P450 oxidoreductase (POR) inhibition.
  • Antiproliferative activity testing in PC3 prostate cancer cells.
  • In silico modeling for structure-activity relationship analysis.

Main Results:

  • A novel compound (comp 2) demonstrated potent CYP17A1 inhibition (IC50 = 1.2 µM).
  • Compound 2 exhibited comparable potency to abiraterone and selectivity against off-target enzymes.
  • Structure-activity relationship data provided insights into the novel non-steroidal compound class.

Conclusions:

  • The study identified potent and selective non-steroidal CYP17A1 inhibitors based on a benzimidazole scaffold.
  • Compound 2 represents a promising lead candidate for further development in prostate cancer therapy.
  • The findings contribute to understanding the structure-activity relationships for this class of anti-cancer agents.
Keywords:
CYP17A1cytochrome P450 17A1enzyme inhibitionprostate cancer

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