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Updated: Jul 8, 2025

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

Martyn C Henry1, Christopher M Riley1, Irene Hunter2

  • 1Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.

ACS Medicinal Chemistry Letters
|December 20, 2023
PubMed

Insights

Researchers identified a new compound, indazole analogue 16, that shows promise for treating castration-resistant prostate cancer (CRPC) by targeting the androgen receptor N-terminal domain.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Androgen receptor (AR) is a key driver in prostate cancer.
  • Current anti-androgen therapies face resistance, leading to castration-resistant prostate cancer (CRPC).
  • The AR N-terminal domain (NTD) is a potential therapeutic target, especially with AR mutations.

Purpose of the Study:

  • To identify novel inhibitors targeting the AR NTD.
  • To develop new therapeutic strategies for CRPC, particularly in cases of resistance and mutation.

Main Methods:

  • Screening identified biaryl isoxazole compound 7 as a weak AR NTD inhibitor.
  • Synthesis of a biaryl analogue library.
  • Structure-activity relationship (SAR) studies using VCaP cell-based assays.

Main Results:

  • Indazole analogue 16 demonstrated increased potency compared to compound 7.
  • Analogue 16 possesses favorable physicochemical and pharmacokinetic properties.
  • Compound 16 serves as a promising starting point for CRPC drug development.

Conclusions:

  • Indazole analogue 16 is a potential therapeutic candidate for CRPC.
  • Targeting the AR NTD offers a viable strategy against resistant prostate cancer.
  • Further optimization of analogue 16 could lead to effective CRPC treatments.

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